PI3K/AKT/mTOR Signaling Pathway in Breast Cancer: From Molecular Landscape to Clinical Aspects
<p>The PI3K/AKT/mTOR signaling pathway. PI3K is activated by the binding of ligands (insulin, growth factors, hormones) to RTKs, but also to GPCR (chemokines). Once activated, this protein kinase will catalyze the phosphorylation of PIP2 to PIP3. AKT is recruited to the plasma membrane where it undergoes two phosphorylation processes, one catalyzed by PDK1 at the level of threonine residue and the second reaction being catalyzed by mTORC2. Once activated by phosphorylation, AKT will phosphorylate other substances such as the mTOR complex, which will be associated in the end with protein synthesis and cell growth. Other phosphorylated substrates, such as GSK-3 and Fox01, will be inhibited, associated with cell proliferation and survival. PTEN is the major negative regulator of this signaling pathway involved in PIP3 dephosphorylation.</p> "> Figure 2
<p>The PI3K/AKT/mTOR signaling pathway and breast cancer. The PI3K/AKT/mTOR signaling pathway is activated by ER, but also by EGFR, HER 2, IGFR1R, and FGFR1 at RTKs level. Once activated, protein kinase B or AKT inhibits TSC ½ by phosphorylation, further leading to the inhibition of Rheb and activation of mTORC1. This activation is associated with anti-apoptotic effects, increased gene expression, cell proliferation and angiogenesis. Everolimus and temsirolimus are two analogues of rapamycin that inhibit the activity of mTOR, especially mTORC1, but also mTORC2.</p> ">
Abstract
:1. Breast Cancer–Incidence and Risk Factors
2. Molecular Types of Breast Cancer
- ER-estrogen receptor status.
- PR-progesterone receptor status.
- Note that HR-represents the joint assessment of ER and PR status.
- 3.
- HER2-human epidermal growth factor receptor 2 status.
- HR+/HER2– corresponding to Luminal A subtype.
- HR+/HER2+ corresponding to Luminal B subtype.
- HR−/HER2+ corresponding to HER2 enriched subtype.
- HR−/HER2– corresponding to triple negative subtype.
3. PI3K/AKT/mTOR Signaling Pathway
3.1. PI3K/AKT/mTOR Signaling Pathway Members
3.1.1. PI3K-Phosphatidylinositol 3-Kinase-(Phosphoinositide 3-Kinase)
3.1.2. AKT
3.1.3. mTOR
3.1.4. FoxO1
3.1.5. PTEN
4. PI3K/AKT/mTOR Mutations in Breast Cancer
HER Receptors and Breast Cancers
5. Mechanisms of Endocrine Resistance in Breast Cancer
6. mTOR Inhibitors: Everolimus and Temsirolimus
7. Conclusions
Funding
Conflicts of Interest
References
- Breast Cancer in Men—CDC Report 11 August 2020. Available online: www.cdc.gov/cancer/men (accessed on 6 October 2020).
- Sancho-Garnier, H.; Colonna, M. Épidémiologie des cancers du sein: Breast cancer epidemiology. Presse Med. 2019, 48, 1076–1084. [Google Scholar] [CrossRef]
- Graham, A.C. Breast Cancer Epidemiology and Risk Factors. Medscape Report 26 December 2019. Available online: https://emedicine.medscape.com/article/1697353-overview (accessed on 6 October 2020).
- Ferley, J.; Soerjomatarami, I.; Ervik, M.; Dikshit, R.; Eser, S. Cancer Incidence and Mortality Worldwide; IARC: Lyon, France, 2013.
- National Cancer Institute Surveillance. Epidemiology and End Results Programme (SEER)—Cancer Stat Facts: Female Breast Cancer. 2020. Available online: http://seer.cancer.gov/statfacts/html/breast.html (accessed on 7 October 2020).
- DeSantis, C.E.; Miller, K.D.; Sauer, A.G.; Siegel, R.L. Cancer Statistics for African Americans, 2019. CA Cancer J. Clin. 2017, 69, 211–233. [Google Scholar] [CrossRef][Green Version]
- Surveillance, Epidemiology, and End Results (SEER) Program. SEER*Stat Database: Mortality-All COD, Aggregated with State, Total U.S. (1990–2017) <Early release with Vintage 2017 Katrina/Rita Population Adjustment>; National Cancer Institute, Division of Cancer Control and Population Sciences, Surveillance Research Program: North Bethesda, MD, USA, 2019; Underlying mortality data provided the by National Center for Health Statistics.
- DeSantis, C.E.; Ma, J.; Goding, S.A.; Newman, L.A.; Jemal, A. Breast cancer statistics, 2017: Racial disparity in mortality by state. CA Cancer. J. Clin. 2017, 67, 439–448. [Google Scholar] [CrossRef] [PubMed][Green Version]
- DeSantis, C.E.; Ma, J.; Bryan, L.; Jemal, A. Breast cancer statistics, 2013. CA Cancer. J. Clin. 2014, 64, 52–62. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Ghoncheh, M.; Pournamdar, Z.; Salehiniya, H. Incidence and mortality and epidemiology of breast cancer in the world. Asian Pac. J. Cancer Prev. 2016, 17, 43–46. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Ghoncheh, M.; Mohammadian-Hafshejani, A.; Salehiniya, H. Incidence and mortality of breast cancer and their relationship to development in Asia. Asian Pac. J. Cancer Prev. 2015, 16, 6081–6087. [Google Scholar] [CrossRef][Green Version]
- Bernstein, L.; Ross, R.K. Endogenous hormones and breast cancer risk. Epidemiol. Rev. 1993, 15, 48–65. [Google Scholar] [CrossRef]
- Wu, A.H.; Stanczyk, F.Z.; Seow, A.; Lee, H.P.; Yu, M.C. Soy intake and other lifestyle determinants of serum estrogen levels among postmenopausal Chinese women in Singapore. Cancer Epidemiol. Biomark. Prev. 2002, 11, 844–851. [Google Scholar]
- Thakur, P.; Seam, R.K.; Gupta, M.K.; Gupta, M.; Sharma, M.; Fotedar, V. Breast cancer risk factor evaluation in a Western Himalayan state: A case-control study and comparison with the Western World. South Asian J. Cancer 2017, 6, 106–109. [Google Scholar]
- Colditz, G.A.; Rosner, B. Cumulative risk of breast cancer to age 70 years according to risk factor status: Data from the Nurses’ Health Study. Am. J. Epidemiol. 2000, 152, 950–964. [Google Scholar] [CrossRef][Green Version]
- Giordano, S.H.; Buzdar, A.U.; Hortobagyi, G.N. Breast Cancer in Men. Ann. Intern. Med. 2002, 137, 678–687. [Google Scholar] [CrossRef] [PubMed]
- Meo, S.A.; Suraya, F.; Jamil, B.; Al Rouq, F.; Meo, A.S.; Sattar, K.; Javed, M.; Alasiri, S.A. Association of ABO and Rh blood groups with breast cancer. Saudi J. Biol. Sci. 2017, 24, 1609–1613. [Google Scholar] [CrossRef] [PubMed]
- National Center for Health Statistics. SEER Cancer Statistics Review, 1973–1999; National Cancer Institute: Bethesda, MD, USA, 1998.
- DeSantis, C.E.; Ma, J.; Gaudet, M.M.; Newman, L.A.; Miller, K.D.; Goding, S.A.; Jemal, A.; Siegel, R.L. Breast cancer statistics, 2019. CA Cancer J. Clin. 2019, 69, 438–451. [Google Scholar] [CrossRef] [PubMed]
- Lilienfeld, A.M. The relationship of cancer of the female breast to artificial menopause and marital status. Cancer 1956, 9, 927–934. [Google Scholar] [CrossRef]
- Dai, Q.; Liu, B.; Du, Y. Meta-analysis of the risk factors of breast cancer concerning reproductive factors and oral contraceptive use. Front. Med. China 2009, 3, 452–458. [Google Scholar] [CrossRef]
- Ma, H.; Henderson, K.D.; Sullivan-Halley, J.; Duan, L.; Marshall, S.F.; Ursin, G.; Horn-Ross, P.L.; Largent, J.; Deapen, D.M.; Lacey, J.V., Jr. Pregnancy-related factors and the risk of breast carcinoma in situ and invasive breast cancer among postmenopausal women in the California Teachers Study cohort. Breast Cancer Res. 2010, 12, R35. [Google Scholar] [CrossRef][Green Version]
- Balekouzou, A.; Yin, P.; Pamatika, C.M.; Bekolo, C.E.; Nambei, S.W.; Djeintote, M.; Kota, K.; Mossoro-Kpinde, C.D.; Shu, C.; Yin, M.; et al. Reproductive risk factors associated with breast cancer in women in Bangui: A case-control study. BMC. Women’s Health 2017, 17, 14. [Google Scholar] [CrossRef][Green Version]
- Rosner, B.; Colditz, G.A.; Willett, W.C. Reproductive risk factors in a prospective study of breast cancer: The Nurses’ Health Study. Am. J. Epidemiol. 1994, 139, 819–835. [Google Scholar] [CrossRef][Green Version]
- Rosner, B.; Colditz, G.A.; Martínez, M.E.; Giovannucci, E.L.; Stampfer, M.J.; Hunter, D.J.; Speizer, F.E.; Wing, A.; Willett, W.C. Nurses’ health study: Log-incidence mathematical model of breast cancer incidence. J. Natl. Cancer Inst. 1996, 88, 359–364. [Google Scholar] [CrossRef][Green Version]
- Mahouri, K.; Zahedani, M.D.; Zare, S. Breast cancer risk factors in south of Islamic Republic of Iran: A case-control study. EMHJ—East. Mediterr. Health J. 2007, 13, 1265–1273. [Google Scholar] [CrossRef]
- Kim, Y.; Yoo, K.Y.; Goodman, M.T. Differences in Incidence, Mortality and Survival of Breast Cancer by Regions and Countries in Asia and Contributing Factors. Asian Pac. J. Cancer Prev. 2015, 16, 2857–2870. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Freund, C.; Mirabel, L.; Annane, K.; Mathelin, C. Breastfeeding and breast cancer. Gynecol. Obstet. Fertil. 2005, 33, 739–744. [Google Scholar] [CrossRef] [PubMed]
- Jeong, S.H.; An, Y.S.; Choi, J.Y.; Park, B.; Kang, D.; Lee, M.H.; Han, W.; Noh, D.Y.; Yoo, K.Y.; Park, S.K. Risk reduction of breast cancer by childbirth, breastfeeding, and their interaction in korean women: Heterogeneous effects across menopausal status, hormone receptor status, and pathological subtypes. J. Prev. Med. Public Health 2017, 50, 401–410. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Deng, Y.; Xu, H.; Zeng, X. Induced abortion and breast cancer: An updated meta-analysis. Medicine 2018, 97, e9613. [Google Scholar] [CrossRef] [PubMed]
- Key, T.; Appleby, P.; Barnes, I.; Reeves, G. Endogenous sex hormones and breast cancer in postmenopausal women: Reanalysis of nine prospective studies. J. Natl. Cancer Inst. 2002, 94, 606–616. [Google Scholar]
- Fisher, B.; Costantino, J.P.; Wickerham, D.L.; Redmond, C.K.; Kavanah, M.; Cronin, W.M.; Vogel, V.; Robidoux, A.; Dimitrov, N.; Atkins, J.; et al. Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J. Natl. Cancer Inst. 1998, 90, 1371–1388. [Google Scholar] [CrossRef]
- Eliassen, A.H.; Missmer, S.A.; Tworoger, S.S.; Spiegelman, D.; Barbieri, R.L.; Dowsett, M.; Hankinson, S.E. Endogenous steroid hormone concentrations and risk of breast cancer among premenopausal women. J. Natl. Cancer Inst. 2006, 98, 1406–1415. [Google Scholar] [CrossRef][Green Version]
- Tworoger, S.S.; Eliassen, A.H.; Rosner, B.; Sluss, P.; Hankinson, S.E. Plasma prolactin concentrations and risk of postmenopausal breast cancer. Cancer Res. 2004, 64, 6814–6819. [Google Scholar] [CrossRef][Green Version]
- Toniolo, P.; Bruning, P.F.; Akhmedkhanov, A.; Bonfrer, J.M.; Koenig, K.L.; Lukanova, A.; Shore, R.E.; Zeleniuch-Jacquotte, A. Serum insulin-like growth factor-I and breast cancer. Int. J. Cancer 2000, 88, 828–832. [Google Scholar] [CrossRef]
- Bhadoria, A.; Kapil, U.; Sareen, N.; Singh, P. Reproductive factors and breast cancer: A case-control study in tertiary care hospital of North India. Indian J. Cancer 2013, 50, 316–321. [Google Scholar]
- Fioretti, F.; Tavani, A.; Bosetti, C.; La Vecchia, C.; Negri, E.; Barbone, F.; Talamini, R.; Franceschi, S. Risk factors for breast cancer in nulliparous women. Br. J. Cancer 1999, 79, 1923–1928. [Google Scholar] [CrossRef] [PubMed]
- Marchbanks, P.A.; McDonald, J.A.; Wilson, H.G.; Folger, S.G.; Mandel, M.G.; Daling, J.R.; Bernstein, L.; Malone, K.E.; Ursin, G.; Storm, B.L.; et al. Oral contraceptives and the risk of breast cancer. N. Engl. J. Med. 2002, 346, 2025–2032. [Google Scholar] [CrossRef] [PubMed]
- Zolfaroli, I.; Tarín, J.J.; Cano, A. Hormonal contraceptives and breast cancer: Clinical data. Eur. J. Obstet. Gynecol. Reprod. Biol. 2018, 230, 212–216. [Google Scholar] [CrossRef] [PubMed]
- Collaborative Group of Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: Collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer from 54 epidemiological studies. Lancet 1996, 347, 1713–1727. [Google Scholar] [CrossRef][Green Version]
- Beral, V.; Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003, 362, 419–427. [Google Scholar] [CrossRef]
- Beral, V.; Bull, D.; Doll, R.; Key, T.; Peto, R.; Reeves, G. Breast cancer and hormone replacement therapy: Collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997, 350, 1047–1059. [Google Scholar] [CrossRef][Green Version]
- Ross, R.K.; Paganini-Hill, A.; Wan, P.C.; Pike, M.C. Effect of hormone replacement therapy on breast cancer risk: Estrogen versus estrogen plus progestin. J. Natl. Cancer Inst. 2000, 92, 328–332. [Google Scholar] [CrossRef]
- Magnusson, C.; Persson, I.; Adami, H.O. More about: Effect of hormone replacement therapy on breast cancer risk: Estrogen versus estrogen plus progestin. J. Natl. Cancer Inst. 2000, 92, 1183–1184. [Google Scholar] [CrossRef][Green Version]
- Colditz, G.A. Estrogen, estrogen plus progestin therapy, and risk of breast cancer. Clin. Cancer Res. 2005, 11, 909s–917s. [Google Scholar]
- Taheripanah, R.; Balash, F.; Anbiaee, R.; Mahmoodi, M.; Akbari, S.A. Breast Cancer and Ovulation Induction Treatments. Clin. Breast Cancer 2018, 18, 395–399. [Google Scholar] [CrossRef]
- Brinton, L.A.; Scoccia, B.; Moghissi, K.S.; Westhoff, C.L.; Althuis, M.D.; Mabie, J.E.; Lamb, E.J. Breast cancer risk associated with ovulation-stimulating drugs. Hum. Reprod. 2004, 19, 2005–2013. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Rojas, K.; Stuckey, A. Breast Cancer Epidemiology and Risk Factors. Clin. Obstet. Gynecol. 2016, 59, 651–672. [Google Scholar] [CrossRef] [PubMed]
- Metcalfe, K.A.; Finch, A.; Poll, A.; Horsman, D.; Kim-Sing, C.; Scott, J.; Royer, R.; Sun, P.; Narod, S.A. Breast cancer risks in women with a family history of breast or ovarian cancer who have tested negative for a BRCA1 or BRCA2 mutation. Br. J. Cancer 2009, 100, 421–425. [Google Scholar] [CrossRef] [PubMed]
- Cobain, E.F.; Milliron, K.J.; Merajver, S.D. Updates on breast cancer genetics: Clinical implications of detecting syndromes of inherited increased susceptibility to breast cancer. Semin. Oncol. 2016, 43, 528–535. [Google Scholar] [CrossRef] [PubMed]
- Godet, I.; Gilkes, D.M. BRCA1 and BRCA2 mutations and treatment strategies for breast cancer. Integr. Cancer Sci. Ther. 2017, 4, 1–17. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Ahmed, F.; Mahmood, N.; Shahid, S.; Hussain, Z.; Ahmed, I.; Jalal, A.; Ijaz, B.; Shahid, A.; Mujtaba, G.; Mustafa, T. Mutations in human interferon α2b gene and potential as risk factor associated with female breast cancer. Cancer Biother. Radiopharm. 2016, 31, 199–208. [Google Scholar] [CrossRef]
- Yari, K.; Rahimi, Z.; Moradi, M.T.; Rahimi, Z. The MMP-2-735 C Allele is a risk factor for susceptibility to breast cancer. Asian Pac. J. Cancer Prev. 2014, 15, 6199–6203. [Google Scholar] [CrossRef][Green Version]
- Gunter, M.J.; Hoover, D.R.; Yu, H.; Wassertheil-Smoller, S.; Rohan, T.E.; Manson, J.E.; Li, J.; Ho, G.Y.; Xue, X.; Anderson, G.L.; et al. Insulin, insulin-like growth factor-I, and risk of breast cancer in postmenopausal women. J. Natl. Cancer Inst. 2009, 101, 48–60. [Google Scholar] [CrossRef][Green Version]
- Tabassum, I.; Mahmood, H.; Faheem, M. Type 2 Diabetes Mellitus as a risk factor for female breast cancer in the population of northern Pakistan. Asian Pac. J. Cancer Prev. 2016, 17, 3255–3258. [Google Scholar]
- Larsson, S.C.; Mantzoros, C.S.; Wolk, A. Diabetes mellitus and risk of breast cancer: A meta-analysis. Int. J. Cancer 2007, 121, 856–862. [Google Scholar] [CrossRef]
- Tang, G.H.; Satkunam, M.; Pond, G.R.; Steinberg, G.R.; Blandino, G.; Schünemann, H.J.; Muti, P. Association of metformin with breast cancer incidence and mortality in patients with type 2 diabetes: A GRADE assessed systematic review and meta-analysis. Cancer Epidemiol. Biomark. Prev. 2018, 27, 627–635. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Chen, M.J.; Wu, W.Y.; Yen, A.M.; Fann, J.C.; Chen, S.L.; Chiu, S.Y.; Chen, H.H.; Chiou, S.T. Body mass index and breast cancer: Analysis of a nation-wide population-based prospective cohort study on 1,393,985 Taiwanese women. Int. J. Obes. 2016, 40, 524–530. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Lahmann, P.H.; Hoffmann, K.; Allen, N.; Van Gils, C.H.; Khaw, K.T.; Tehard, B.; Berrino, F.; Tjønneland, A.; Bigaard, J.; Olsen, A. Body size and breast cancer risk: Findings from the European prospective investigation into cancer and nutrition. Int. J. Cancer 2004, 111, 762–771. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Guo, W.; Key, T.J.; Reeves, G.K. Adiposity and breast cancer risk in postmenopausal women: Results from the UK biobank prospective cohort. Int. J. Cancer 2018, 143, 1037–1046. [Google Scholar] [CrossRef]
- Pimentel, I.; Lohmann, A.E.; Goodwin, P.J. Normal weight adiposity and postmenopausal breast cancer risk. JAMA Oncol. 2019, 5, 150–151. [Google Scholar] [CrossRef]
- Taylor, E.F.; Burley, V.J.; Greenwood, D.C.; Cade, J.E. Meat consumption and risk of breast cancer in the UK women’s cohort study. Br. J. Cancer 2007, 96, 1139–1146. [Google Scholar] [CrossRef][Green Version]
- Sieri, S.; Krogh, V.; Ferrari, P.; Berrino, F.; Pala, V.; Thiébaut, A.C.; Tjønneland, A.; Olsen, A.; Overvad, K.; Jakobsen, M.U.; et al. Dietary fat and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition. Am. J. Clin. Nutr. 2008, 88, 1304–1312. [Google Scholar]
- Berkey, C.S.; Rockett, H.R.; Willett, W.C.; Colditz, G.A. Milk, dairy fat, dietary calcium, and weight gain: A longitudinal study of adolescents. Arch. Pediatrics Adolesc. Med. 2005, 159, 543–550. [Google Scholar] [CrossRef][Green Version]
- Hatse, S.; Lambrechts, D.; Verstuyf, A.; Smeets, A.; Brouwers, B.; Vandorpe, T.; Brouckaert, O.; Peuteman, G.; Laenen, A.; Verlinden, L. Vitamin D status at breast cancer diagnosis: Correlation with tumor characteristics, disease outcome, and genetic determinants of vitamin D insufficiency. Carcinogenesis 2012, 33, 1319–1326. [Google Scholar] [CrossRef][Green Version]
- O’Brien, K.M.; Sandler, D.P.; Taylor, J.A.; Weinberg, C.R. Serum vitamin D and risk of breast cancer within five years. Environ. Health Perspect. 2017, 125, 077004. [Google Scholar] [CrossRef]
- Hamajima, N.; Hirose, K.; Tajima, K.; Rohan, T.; Calle, E.E.; Heath, C.W., Jr.; Coates, R.J.; Liff, J.M.; Talamini, R.; Chantarakul, N.; et al. Alcohol, tobacco and breast cancer—Collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease. Br. J. Cancer 2002, 87, 1234–1245. [Google Scholar] [PubMed]
- Romieu, I.; Scoccianti, C.; Chajès, V.; de Batlle, J.; Biessy, C.; Dossus, L.; Baglietto, L.; Clavel-Chapelon, F.; Overvad, K.; Olsen, A.; et al. Alcohol intake and breast cancer in the European prospective investigation into cancer and nutrition. Int. J. Cancer. 2015, 137, 1921–1930. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Luo, J.; Margolis, K.L.; Wactawski-Wende, J.; Horn, K.; Messina, C.; Stefanick, M.L.; Tindle, H.A.; Tong, E.; Rohan, T.E. Association of active and passive smoking with risk of breast cancer among postmenopausal women: A prospective cohort study. BMJ 2011, 342, d1016. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Tong, J.H.; Li, Z.; Shi, J.; Li, H.M.; Wang, Y.; Fu, L.Y.; Liu, Y.P. Passive smoking exposure from partners as a risk factor for ER+/PR+ double positive breast cancer in never-smoking Chinese urban women: A hospital-based matched case control study. PLoS ONE 2014, 9, e97498. [Google Scholar] [CrossRef] [PubMed]
- The Health Consequences of Involuntary Exposure to Tobacco Smoke: A Report of the Surgeon General. 2006. Available online: www.surgeongeneral.gov/library/secondhandsmoke/report/index.html (accessed on 11 October 2020).
- Mctiernan, A.; Kooperberg, C.; White, E.; Wilcox, S.; Coates, R.; Adams-Campbell, L.L.; Woods, N.; Ockene, J. Women’s health initiative cohort study recreational physical activity and the risk of breast cancer in postmenopausal women: The women’s health initiative cohort study. JAMA 2003, 290, 1331–1336. [Google Scholar] [CrossRef] [PubMed]
- Lee, J.A. Meta-analysis of the association between physical activity and breast cancer mortality. Cancer Nurs. 2019, 42, 271–285. [Google Scholar] [CrossRef] [PubMed]
- Benabu, J.C.; Stoll, F.; Gonzalez, M.; Mathelin, C. Night work, shift work: Breast cancer risk factor? Gynecol. Obstet. Fertil. 2015, 43, 791–799. [Google Scholar] [CrossRef]
- Stevens, R.G.; Davis, S. The melatonin hypothesis: Electric power and breast cancer. Environ. Health Perspect. 1996, 104 (Suppl. 1), 135–140. [Google Scholar]
- Megdal, S.P.; Kroenke, C.H.; Laden, F.; Pukkala, E.; Schernhammer, E.S. Night work and breast cancer risk: A systematic review and meta-analysis. Eur. J. Cancer 2005, 41, 2023–2032. [Google Scholar] [CrossRef]
- Orsini, M.; Trétarre, B.; Daurès, J.P.; Bessaoud, F. Individual socioeconomic status and breast cancer diagnostic stages: A French case-control study. Eur. J. Public Health 2016, 26, 445–450. [Google Scholar] [CrossRef][Green Version]
- Lundqvist, A.; Andersson, E.; Ahlberg, I.; Nilbert, M.; Gerdtham, U. Socioeconomic inequalities in breast cancer incidence and mortality in Europe-a systematic review and meta-analysis. Eur. J. Public Health 2016, 26, 804–813. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Abdulrahman, G.O.; Rahman, G.A. Epidemiology of Breast Cancer in Europe and Africa. J. Cancer Epidemiol. 2012, 2012, 915610. [Google Scholar] [CrossRef] [PubMed]
- Hartmann, L.C.; Sellers, T.A.; Frost, M.H.; Lingle, W.L.; Degnim, A.C.; Ghosh, K.; Vierkant, R.A.; Maloney, S.D.; Pankratz, V.S.; Hillman, D.W.; et al. Benign breast disease and the risk of breast cancer. N. Engl. J. Med. 2005, 353, 229–237. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Brinton, L.A.; Lubin, J.H.; Murray, M.C.; Colton, T.; Hoover, R.N. Mortality rates among augmentation mammoplasty patients: An update. Epidemiology 2006, 17, 162–169. [Google Scholar] [CrossRef]
- Boyd, N.F.; Guo, H.; Martin, L.J.; Sun, L.; Stone, J.; Fishell, E.; Jong, R.A.; Hislop, G.; Chiarelli, A.; Minkin, S.; et al. Mammographic density and the risk and detection of breast cancer. N. Engl. J. Med. 2007, 356, 227–236. [Google Scholar] [CrossRef][Green Version]
- Nazari, S.S.; Mukherjee, P. An overview of mammographic density and its association with breast cancer. Breast Cancer 2018, 25, 259–267. [Google Scholar] [CrossRef][Green Version]
- Tamimi, R.M.; Byrne, C.; Colditz, G.A.; Hankinson, S.E. Endogenous hormone levels, mammographic density, and subsequent risk of breast cancer in postmenopausal women. J. Natl. Cancer Inst. 2007, 99, 1178–1187. [Google Scholar] [CrossRef][Green Version]
- Land, C.E.; Tokunaga, M.; Koyama, K.; Soda, M.; Preston, D.L.; Nishimori, I.; Tokuoka, S. Incidence of female breast cancer among atomic bomb survivors, Hiroshima and Nagasaki, 1950–1990. Radiat. Res. 2003, 160, 707–717. [Google Scholar] [CrossRef]
- Henderson, T.O.; Moskowitz, C.S.; Chou, J.F.; Bradbury, A.R.; Neglia, J.P.; Dang, C.T.; Onel, K.; Friedman, D.N.; Bhatia, S.; Strong, L.C.; et al. Breast cancer risk in childhood cancer survivors without a history of chest radiotherapy: A report from the Childhood Cancer Survivor Study. J. Clin. Oncol. 2016, 34, 910–918. [Google Scholar] [CrossRef]
- Horwich, A.; Swerdlow, A.J. Second primary breast cancer after Hodgkin’s disease. Br. J. Cancer 2004, 90, 294–298. [Google Scholar] [CrossRef][Green Version]
- Perou, C.M.; Sørlie, T.; Eisen, M.B.; Van de Rijn, M.; Jeffrey, S.S.; Rees, C.A.; Pollack, J.R.; Ross, D.T.; Johnsen, H.; Akslen, L.A.; et al. Molecular portraits of human breast tumors. Nature 2000, 17, 747–752. [Google Scholar] [CrossRef] [PubMed]
- Howlader, N.; Altekruse, S.F.; Li, C.I.; Chen, V.W.; Clarke, C.A.; Ries, L.A.; Cronin, K.A. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J. Natl. Cancer Inst. 2014, 106, dju055. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Dwivedi, S.; Purohit, P.; Misra, R.; Lingeswaran, M.; Vishnoi, J.R.; Pareek, P.; Sharma, P.; Misra, S. Application of single-cell omics in breast cancer in single-cell omics. Appl. Biomed. Agric. 2019, 2, 69–103. [Google Scholar]
- Aftimos, P.; Azim, H.A., Jr.; Sotiriou, C. Molecular biology of breast cancer. In Molecular Pathology, 2nd ed.; Coleman, W.B., Tsongalis, G.J., Eds.; Academic Press: Cambridge, MA, USA, 2018; pp. 569–588. [Google Scholar]
- Lehmann, B.D.; Bauer, J.A.; Chen, X.; Sanders, M.E.; Chakravarthy, A.B.; Shyr, Y.; Pietenpol, J.A. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J. Clin. Invest. 2011, 121, 2750–2767. [Google Scholar] [CrossRef][Green Version]
- Colozza, M.; Azambuja, E.; Cardoso, F.; Sotiriou, C.; Larsimont, D.; Piccart, M.J. Proliferative markers as prognostic and predictive tools in early breast cancer: Where are we now? Ann. Oncol. 2005, 16, 1723–1739. [Google Scholar] [CrossRef]
- Lim, W.; Mayer, B.; Pawson, T. Cell Signaling: Principles and Mechanisms; Garland Science: New York, NY, USA, 2015. [Google Scholar]
- Hancock, J.F. Ras proteins: Different signals from different locations. Nat. Rev. Mol. Cell Biol. 2003, 4, 373–384. [Google Scholar] [CrossRef]
- Bourne, H.R.; Sanders, D.A.; McCormick, F. The GTPase superfamily: A conserved switch for diverse cell functions. Nature 1990, 348, 125–132. [Google Scholar] [CrossRef]
- Paduch, M.; Jelen, F.; Otlewski, J. Structure of small G proteins and their regulators. Acta Biochim. Pol. 2001, 48, 829–850. [Google Scholar] [CrossRef][Green Version]
- Yudushkin, I. Getting the Akt together: Guiding intracellular Akt activity by PI3K. Biomolecules 2019, 9, 67. [Google Scholar] [CrossRef][Green Version]
- Yu, X.; Long, Y.C.; Shen, H.M. Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy. Autophagy 2015, 11, 1711–1728. [Google Scholar] [CrossRef][Green Version]
- Lehninger, A.; Nelson, D.L.; Cox, M.C.; Freeman, W.H. Lehninger Principles of Biochemistry; W.H. Freeman: New York, NY, USA, 2012. [Google Scholar]
- Balla, T. Phosphoinositides: Tiny lipids with giant impact on cell regulation. Physiol. Rev. 2013, 93, 1019–1137. [Google Scholar] [CrossRef] [PubMed]
- Braccini, L.; Ciraolo, E.; Campa, C.C.; Perino, A.; Longo, D.L.; Tibolla, G.; Pregnolato, M.; Cao, Y.; Tassone, B.; Damilano, F.; et al. PI3K-C2γ is a Rab5 effector selectively controlling endosomal Akt2 activation downstream of insulin signalling. Nat. Commun. 2015, 6, 7400. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Falasca, M.; Hughes, W.E.; Dominguez, V.; Sala, G.; Fostira, F.; Fang, M.Q.; Cazzolli, R.; Shepherd, P.R.; James, D.E.; Maffucci, T. The role of phosphoinositide 3-kinase C2α in insulin signaling. J. Biol. Chem. 2007, 282, 28226–28236. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Backer, J. The intricate regulation and complex functions of the Class III phosphoinositide 3-kinase Vps34. Biochem. J. 2016, 473, 2251–2271. [Google Scholar] [CrossRef]
- Manning, B.D.; Toker, A. AKT/PKB signaling: Navigating the network. Cell 2017, 169, 381–405. [Google Scholar] [CrossRef][Green Version]
- Dummler, B.; Hemmings, B.A. Physiological roles of PKB/Akt isoforms in development and disease. Biochem. Soc. Trans. 2007, 35, 231–235. [Google Scholar] [CrossRef]
- Szymonowicz, K.; Oeck, S.; Malewicz, N.M.; Jendrossek, V. New insights into protein kinase B/Akt signaling: Role of localized Akt activation and compartment-specific target proteins for the cellular radiation response. Cancers 2018, 10, 78. [Google Scholar] [CrossRef][Green Version]
- Revathidevi, S.; Munirajan, A.K. Akt in cancer: Mediator and more. Semin. Cancer Biol. 2019, 59, 80–91. [Google Scholar] [CrossRef]
- Risso, G.; Blaustein, M.; Pozzi, B.; Mammi, P.; Srebrow, A. Akt/PKB: One kinase, many modifications. Biochem. J. 2015, 468, 203–214. [Google Scholar] [CrossRef]
- Luo, C.T.; Li, M. Foxo transcription factors in T cell biology and tumor immunity. Semin. Cancer Biol. 2018, 50, 13–20. [Google Scholar] [CrossRef]
- Arcaro, A.; Guerreiro, A.S. The phosphoinositide 3-kinase pathway in human cancer: Genetic alterations and therapeutic implications. Curr. Genom. 2007, 8, 271–306. [Google Scholar] [CrossRef] [PubMed]
- Patel, P.; Woodgett, J.R. Glycogen Synthase Kinase 3: A Kinase for All Pathways? Curr. Top. Dev. Biol. 2017, 123, 277–302. [Google Scholar] [PubMed]
- Dokken, B.B.; Sloniger, J.A.; Henriksen, E.J. Acute selective glycogen synthase kinase-3 inhibition enhances insulin signaling in prediabetic insulin-resistant rat skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 2005, 288, E1188–E1194. [Google Scholar] [CrossRef] [PubMed]
- Lochhead, P.A.; Coghlan, M.; Rice, S.Q.; Sutherland, C. Inhibition of GSK-3 selectively reduces glucose-6-phosphatase and phosphatase and phosphoenolypyruvate carboxykinase gene expression. Diabetes 2001, 50, 937–946. [Google Scholar] [CrossRef][Green Version]
- Wei, X.; Luo, L.; Chen, J. Roles of mTOR signaling in tissue regeneration. Cells 2019, 8, 1075. [Google Scholar] [CrossRef][Green Version]
- Kakumoto, K.; Ikeda, J.; Okada, M.; Morii, E.; Oneyama, C. mLST8 promotes mTOR-mediated tumor progression. PLoS ONE 2015, 10, e0119015. [Google Scholar] [CrossRef]
- Mahoney, R.E.; Azpurua, J.; Eaton, B.A. Insulin signaling controls neurotransmission via the 4eBP-dependent modification of the exocytotic machinery. eLife 2016, 5, e16807. [Google Scholar] [CrossRef][Green Version]
- Berchtold, D.; Walther, T.C. TORC2 Plasma membrane localization is essential for cell viability and restricted to a distinct domain. Mol. Biol. Cell 2009, 20, 1565–1575. [Google Scholar] [CrossRef][Green Version]
- Liu, P.; Gan, W.; Inuzuka, H.; Lazorchak, A.S.; Gao, D.; Arojo, O.; Liu, D.; Wan, L.; Zhai, B.; Yu, Y.; et al. Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis. Nat. Cell Biol. 2013, 15, 1340–1350. [Google Scholar] [CrossRef]
- Hollenhorst, P.C.; Bose, M.E.; Mielke, M.R.; Müller, U.; Fox, C.A. Forkhead genes in transcriptional silencing, cell morphology and the cell cycle. Overlapping and distinct functions for FKH1 and FKH2 in Saccharomyces cerevisiae. Genetics 2000, 154, 1533–1548. [Google Scholar]
- Cabrera-Ortega, A.; Feinberg, D.; Liang, Y.; Rossa, J.C.; Graves, D.T. The role of Forkhead Box 1 (FOXO1) in the immune system: Dendritic cells, T cells, B cells, and hematopoietic stem cells. Crit. Rev. Immunol. 2017, 37, 1–13. [Google Scholar] [CrossRef] [PubMed]
- Ma, Z.; Xin, Z.; Hu, W.; Jiang, S.; Yang, Z.; Yan, X.; Li, X.; Yang, Y.; Chen, F. Forkhead box O proteins: Crucial regulators of cancer EMT. Semin. Cancer Biol. 2018, 50, 21–31. [Google Scholar] [CrossRef] [PubMed]
- Maiese, K. Forkhead transcription factors: Formulating a FOXO target for cognitive loss. Curr. Neurovascular Res. 2017, 14, 415–420. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Cretella, D.; Digiacomo, G.; Giovannetti, E.; Cavazzoni, A. PTEN alterations as a potential mechanism for tumor cell escape from PD-1/PD-L1 inhibition. Cancers 2019, 11, 1318. [Google Scholar] [CrossRef][Green Version]
- Luongo, F.; Colonna, F.; Calapà, F.; Vitale, S.; Fiori, M.E.; De Maria, R. PTEN tumor-suppressor: The dam of stemness in cancer. Cancers 2019, 11, 1076. [Google Scholar] [CrossRef][Green Version]
- Naderali, E.; Khaki, A.A.; Rad, J.S.; Alihemmati, A.; Rahmati, M.; Nozad-Charoudeh, H. Regulation and modulation of PTEN activity. Mol. Biol. Rep. 2018, 45, 2869–2881. [Google Scholar] [CrossRef]
- Maehama, T.; Taylor, G.S.; Dixon, J.E. PTEN and myotubularin: Novel phosphoinositide phosphatases. Annu. Rev. Biochem. 2001, 70, 247–279. [Google Scholar] [CrossRef]
- Nguyen, K.T.; Tajmir, P.; Lin, C.H.; Liadis, N.; Zhu, X.D.; Eweida, M.; Tolasa-Karaman, G.; Cai, F.; Wang, R.; Kitamura, T.; et al. Essential role of PTEN in body size determination and pancreatic beta-cell homeostasis in vivo. Mol. Cell. Biol. 2006, 26, 4511–4518. [Google Scholar] [CrossRef][Green Version]
- Abraham, J. PI3K/AKT/mTOR pathway inhibitors: The ideal combination partners for breast cancer therapies? Expert Rev. Anticancer Ther. 2015, 15, 51–68. [Google Scholar] [CrossRef]
- Miller, T.W.; Rexer, B.N.; Garrett, J.T.; Arteaga, C.L. Mutations in the phosphatidylinositol 3-kinase pathway: Role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res. 2011, 13, 224. [Google Scholar] [CrossRef][Green Version]
- Chalhoub, C.; Baker, S.J. PTEN and the PI3-kinase pathway in cancer. Annu. Rev. Pathol. 2009, 4, 127–150. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Martínez-Sáez, O.; Chic, N.; Pascual, T.; Adamo, B.; Vidal, M.; González-Farré, B.; Sanfeliu, E.; Schettini, F.; Conte, B.; Brasó-Maristany, F.; et al. Frequency and spectrum of PIK3CA somatic mutations in breast cancer. Breast Cancer Res. 2020, 22, 45. [Google Scholar] [CrossRef] [PubMed]
- Vasan, N.; Razavi, P.; Johnson, J.L.; Shao, H.; Shah, H.; Antoine, A.; Ladewig, E.; Gorelick, A.N.; Lin, T.-Y.; Toska, E.; et al. Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors. Science 2019, 366, 714–723. [Google Scholar] [CrossRef] [PubMed]
- Xing, Y.; Lin, N.U.; Maurer, M.A.; Chen, H.; Mahvash, A.; Sahin, A.; Akcakanat, A.A.; Yisheng, L.; Abramson, V.; Litton, J.; et al. Phase II trial of AKT inhibitor MK-2206 in patients with advanced breast cancer who have tumors with PIK3CA or AKT mutations, and/or PTEN loss/PTEN mutation. Breast Cancer Res. 2019, 21, 78. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Samuels, Y.; Wang, Z.; Bardelli, A.; Ptak, N.J.; Szabo, S.; Yan, H.; Gazdar, A.; Powell, S.M.; Riggins, G.J.; Willson, J.K.V.; et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004, 304, 554. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Samuels, Y.; Diaz, L.A.; Schmidt-Kittler, O.; Cummins, J.M.; Delong, L.; Cheong, I.; Rago, C.; Huso, D.L.; Lengauer, C.; Kinzler, K.W.; et al. Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 2005, 7, 561–573. [Google Scholar] [CrossRef][Green Version]
- Karakas, B.; Bachman, K.E.; Park, B.H. Mutation of the PIK3CA oncogene in human cancers. Br. J. Cancer 2006, 94, 455–459. [Google Scholar] [CrossRef][Green Version]
- Rand, A.; Yardena, S. PIK3CA in cancer: The past 30 years. Semin. Cancer. Biol. 2019, 59, 36–49. [Google Scholar]
- Saal, L.H.; Holm, K.; Maurer, M.; Memeo, L.; Su, T.; Wang, X.; Yu, J.S.; Malmström, P.O.; Mansukhani, M.; Enoksson, J.; et al. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res. 2005, 1, 2554–2559. [Google Scholar] [CrossRef][Green Version]
- Bachman, K.E.; Argani, P.; Samuels, Y.; Silliman, N.; Ptak, J.; Szabo, S.; Konishi, H.; Karakas, B.; Blair, B.G.; Lin, C.; et al. The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol. Ther. 2004, 3, 772–775. [Google Scholar] [CrossRef][Green Version]
- Stemke-Hale, K.; Gonzalez-Angulo, A.M.; Lluch, A.; Neve, R.M.; Kuo, W.-L.; Davies, M.; Carey, M.; Yinghui, G.; Guan, Y.; Sahin, A.; et al. An Integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res. 2008, 68, 6084–6091. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Li, S.Y.; Rong, M.; Grieu, F.; Iacopetta, B. PIK3CA mutations in breast cancer are associated with poor outcome. Breast Cancer Res. Treat. 2005, 96, 91–95. [Google Scholar] [CrossRef] [PubMed]
- Tan, M.-H.; Mester, J.L.; Ngeow, J.; Rybicki, L.A.; Orloff, M.S.; Eng, C. Lifetime cancer risks in individuals with germline PTEN mutations. Clin. Cancer Res. 2012, 18, 400–407. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Carbognin, L.; Miglietta, F.; Paris, I.; Dieci, M.V. Prognostic and predictive implications of PTEN in breast cancer: Unfulfilled promises but intriguing perspectives. Cancers 2019, 11, 1401. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Sobral-Leite, M.; Salomon, I.; Opdam, M.; Kruger, D.T.; Beelen, K.J.; Van Der Noort, V.; Van Vlierberghe, R.L.P.; Blok, E.J.; Giardiello, D.; Sanders, J.; et al. Cancer-immune interactions in ER-positive breast cancers: PI3K pathway alterations and tumor-infiltrating lymphocytes. Breast Cancer Res. 2019, 21, 90. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Zardavas, D.; Te Marvelde, L.; Milne, R.L.; Fumagalli, D.F.; Fountzilas, G.; Kotoula, V.; Razis, E.; Papaxoinis, G.; Joensuu, H.; Moynahan, M.E.; et al. Tumor PIK3CA genotype and prognosis in early-stage breast cancer: A pooled analysis of individual patient data. J. Clin. Oncol. 2018, 1, 981–990. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Ling, D.; Xuehua, Z.; Yun, S.; Jiemin, W.; Xiaorong, Z.; Jiayuan, L.; Min, H.; Hong, Z. Prevalence and prognostic role of PIK3CA/AKT1 mutations in chinese breast cancer patients. Cancer. Res. Treat. 2019, 51, 128–140. [Google Scholar]
- Anderson, A.J.; Mollon, L.E.; Dean, J.L.; Warholak, T.L.; Aizer, A.; Platt, E.A.; Tang, D.H.; Lisa, E.; Davis, L.E. A systematic review of the prevalence and diagnostic workup of PIK3CA mutations in HR+/HER2− metastatic breast cancer. Int. J. Breast. Cancer 2020, 2020, 3759179. [Google Scholar] [CrossRef]
- Lehmann, B.D.; Bauer, J.A.; Schafer, J.M.; Pendleton, C.S.; Tang, L.; Johnson, K.C.; Chen, X.; Balko, J.M.; Gómez, H.L.; Arteaga, C.L.; et al. PIK3CA mutations in androgen receptor-positive triple negative breast cancer confer sensitivity to the combination of PI3K and androgen receptor inhibitors. Breast Cancer Res. 2014, 8, 406. [Google Scholar] [CrossRef][Green Version]
- Dieci, M.V.; Miglietta, F.; Griguolo, G.; Guarneri, V. Biomarkers for HER2-positive metastatic breast cancer: Beyond hormone receptors. Cancer Treat. Rev. 2020, 88, 102064. [Google Scholar] [CrossRef]
- Toss, A.; Cristofanilli, M. Molecular characterization and targeted therapeutic approaches in breast cancer. Breast Cancer Res. 2015, 17, 60. [Google Scholar] [CrossRef] [PubMed]
- Hsu, J.H.; Hung, M.C. The role of HER2, EGFR, and other receptor tyrosine kinases in breast cancer. Cancer Metastasis Rev. 2016, 35, 575–588. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Mitri, Z.; Constantine, T.; O’Regan, R. The HER2 receptor in breast cancer: Pathophysiology, clinical use, and new advances in therapy. Chemother. Res. Pract. 2012, 2012, 743193. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Gagliato, D.D.M.; Jardim, D.L.F.; Marchesi, M.S.P.; Hortobagyi, G.N. Mechanisms of resistance and sensitivity to anti-HER2 therapies in HER2+ breast cancer. Oncotarget 2016, 7, 64431–64446. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Schettini, F.; Buono, G.; Cardalesi, C.; Desideri, I.; De Placido, S.; Del Mastro, L. Hormone receptor/human epidermal growth factor receptor 2-positive breast cancer: Where we are now and where we are going. Cancer Treat. Rev. 2016, 46, 20–26. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Babak, N.; Hamid, M.; Zhixiang, W. Mechanisms underlying the action and synergism of trastuzumab and pertuzumab in targeting HER2-positive breast cancer. Cancers 2018, 10, 342. [Google Scholar]
- Kechagioglou, P.; Papi, R.; Provatopoulou, X.; Kalogera, E.; Papadimitriou, E.; Grigoropoulos, P.; Nonni, A.; Zografos, G.; Kyriakidis, D.A.; Gounaris, A. Tumor suppressor PTEN in breast cancer: Heterozygosity, mutations and protein expression. Anticancer Res. 2014, 34, 1387–1400. [Google Scholar]
- Ruiz-Saenz, A.; Dreyer, C.; Campbell, M.R.; Steri, V.; Gulizia, N.; Moasser, M. HER2 amplification in tumors activates PI3K/AKT signaling independent of HER3. Cancer Res. 2018, 78, 3655–3658. [Google Scholar] [CrossRef][Green Version]
- Yang, Z.; Li, N.; Li, X.; Lei, L.; Wang, X. The prognostic impact of hormonal receptor and HER-2 expression discordance in metastatic breast cancer patients. OncoTargets Ther. 2020, 13, 853–863. [Google Scholar] [CrossRef][Green Version]
- Clarke, R.; Tyson, J.J.; Dixon, J.M. Endocrine resistance in breast cancer-An overview and update. Mol. Cell. Endocrinol. 2015, 418, 220–234. [Google Scholar] [CrossRef][Green Version]
- García-Becerra, R.; Santos-Martínez, N.; Díaz, L.; Camacho, J. Mechanisms of resistance to endocrine therapy in breast cancer: Focus on signaling pathways, miRNAs and genetically based resistance. Int. J. Mol. Sci. 2013, 14, 108–145. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Osborne, C.K.; Schiff, R. Mechanisms of endocrine resistance in breast cancer. Annu. Rev. Med. 2011, 62, 233–247. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Ghayad, S.E.; Vendrell, J.A.; Larbi, S.B.; Dumontet, C.; Bieche, I.; Cohen, P.A. Endocrine resistance associated with activated ErbB system in breast cancer cells is reversed by inhibiting MAPK or PI3K/Akt signaling pathways. Int. J. Cancer 2010, 126, 545–562. [Google Scholar] [CrossRef] [PubMed]
- Johnston, S.R. Enhancing endocrine therapy for hormone receptor-positive advanced breast cancer: Cotargeting signaling pathways. J. Natl. Cancer Inst. 2015, 107, djv212. [Google Scholar] [CrossRef]
- Lange, C.A.; Yee, D. Killing the second messenger: Targeting loss of cell cycle control in endocrine-resistant breast cancer. Endocr.-Relat. Cancer 2011, 18, C19–C24. [Google Scholar] [CrossRef]
- Jeselsohn, R.; Buchwalter, G.; De Angelis, C.; Brown, M.; Schiff, R. ESR1 mutations-a mechanism for acquired endocrine resistance in breast cancer. Nat. Rev. Clin. Oncol. 2015, 12, 573. [Google Scholar] [CrossRef][Green Version]
- Giuliano, M.; Schiff, R.; Osborne, C.K.; Trivedi, M.V. Biological mechanisms and clinical implications of endocrine resistance in breast cancer. Breast 2011, 20, S42–S49. [Google Scholar] [CrossRef]
- Cook, K.L.; Shajahan, A.N.; Clarke, R. Autophagy and endocrine resistance in breast cancer. Expert Rev. Anticancer Ther. 2011, 11, 1283–1294. [Google Scholar] [CrossRef]
- Mackey, J.; Kaufman, B.; Clemens, M.; Bapsy, P.P. Trastuzumab prolongs progression free survival in hormone-dependent and HER2-positive metastatic breast cancer. In Breast Cancer Research and Treatment, Proceedings of the 29th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, USA, 14–17 December 2006; Springer: Berlin/Heidelberg, Germany, 2006; Volume 100. [Google Scholar]
- Merenbakh-Lamin, K.; Ben-Baruch, N.; Yeheskel, A.; Dvir, A.; Soussan-Gutman, L.; Jeselsohn, R.; Rizel, S. D538G mutation in estrogen receptor-α: A novel mechanism for acquired endocrine resistance in breast cancer. Cancer Res. 2013, 73, 6856–6864. [Google Scholar] [CrossRef][Green Version]
- O’Regan, R.M.; Paplomata, E. New and emerging treatments for estrogen receptor-positive breast cancer: Focus on everolimus. Ther. Clin. Risk Manag. 2013, 9, 27–36. [Google Scholar] [CrossRef][Green Version]
- Hoppe, R.; Achinger-Kawecka, J.; Winter, S.; Fritz, P.; Lo, W.-Y.; Schroth, W.; Brauch, H. Increased expression of miR-126 and miR-10a predict prolonged relapse-free time of primary oestrogen receptor-positive breast cancer following tamoxifen treatment. Eur. J. Cancer 2013, 49, 3598–3608. [Google Scholar] [CrossRef] [PubMed]
- Kovalchuk, O.; Filkowski, J.; Meservy, J.; Ilnytskyy, Y.; Tryndyak, V.P.; Chekhun, V.F.; Pogribny, I.P. Involvement of microRNA-451 in resistance of the MCF-7 breast cancer cells to chemotherapeutic drug doxorubicin. Mol. Cancer Ther. 2008, 7, 2152–2159. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Luqmani, Y.A.; Al Saleh, S.; Sharaf, L.H. Signalling pathways involved in endocrine resistance in breast cancer and associations with epithelial to mesenchymal transition. Int. J. Oncol. 2011, 38, 1197–1217. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Creighton, C.J.; Fu, X.; Hennessy, B.T.; Casa, A.J.; Zhang, Y.; Gonzalez-Angulo, A.M.; Lluch, A.; Gray, J.W.; Brown, P.H.; Hilsenbeck, S.G.; et al. Proteomic and transcriptomic profiling reveals a link between the PI3K pathway and lower estrogen-receptor (ER) levels and activity in ER+ breast cancer. Breast Cancer Res. 2010, 12, R40. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Cavazzoni, A.; Bonelli, M.; Fumarola, C.; La Monica, S.; Airoud, K.; Bertoni, R.; Alfieri, R.; Galetti, M.; Tramonti, S.; Galvani, E.; et al. Overcoming acquired resistance to letrozole by targeting the PI3K/AKT/mTOR pathway in breast cancer cell clones. Cancer Lett. 2012, 323, 77–87. [Google Scholar] [CrossRef] [PubMed]
- Johnston, S.R. New strategies in estrogen receptor-positive breast cancer. Clin. Cancer Res. 2010, 16, 1979–1987. [Google Scholar] [CrossRef][Green Version]
- Houghton, P.J. Everolimus. Clin. Cancer Res. 2010, 16, 1368–1372. [Google Scholar] [CrossRef][Green Version]
- Lee, J.J.X.; Loh, K.; Yap, Y.-S. PI3K/Akt/mTOR inhibitors in breast cancer. Cancer Biol. Med. 2015, 12, 342–354. [Google Scholar]
- Baselga, J.; Campone, M.; Piccart, M.; Burris, H.A., III; Rugo, H.S.; Sahmoud, T.; Noguchi, S.; Gnan, M.; Pritchard, K.I.; Lebrun, F.; et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 2012, 366, 520–529. [Google Scholar] [CrossRef][Green Version]
- Schmid, P.; Zaiss, M.; Harper-Wynne, C.; Ferreira, M.; Dubey, S.; Chan, S.; Ruiz, I. Fulvestrant plus vistusertib vs. fulvestrant plus everolimus vs. fulvestrant alone for women with hormone receptor–positive metastatic breast cancer: The MANTA phase 2 randomized clinical trial. JAMA Oncol. 2019, 5, 1556–1563. [Google Scholar] [CrossRef]
- Bachelot, T.; Bourgier, C.; Cropet, C.; Ray-Coquard, I.; Ferrero, J.-M.; Freyer, G.; Abadie-Lacourtoisie, S.; Eymard, J.-C.; Debled, M.; Spaëth, D.; et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2–negative metastatic breast cancer with prior exposure to aromatase inhibitors: A GINECO Study. J. Clin. Oncol. 2012, 30, 2718–2724. [Google Scholar] [CrossRef] [PubMed]
- André, F.; O’Regan, R.; Ozguroglu, M.; Toi, M.; Xu, B.; Jerusalem, G.; Masuda, N.; Wilks, S.; Arena, F.; Isaacs, C.; et al. Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): A randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2014, 15, 580–591. [Google Scholar] [CrossRef]
- Hurvitz, S.A.; Dalenc, F.; Campone, M.; O’Regan, R.M.; Tjan-Heijnen, V.C.; Gligorov, J.; Llombart, A.; Jhangiani, H.; Mirshahidi, H.R.; Tan-Chiu, E.; et al. A phase 2 study of everolimus combined with trastuzumab and paclitaxel in patients with HER2-overexpressing advanced breast cancer that progressed during prior trastuzumab and taxane therapy. Breast Cancer Res. Treat. 2013, 141, 437–446. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Boulay, A.; Rudloff, J.; Ye, J.; Zumstein-Mecker, S.; O’Reilly, T.; Evans, D.B.; Chen, S.; Lane, H.A. Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer. Clin. Cancer Res. 2005, 11, 5319–5328. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Yi, Z.; Ma, F.; Liu, B.; Guan, X.; Li, L.; Li, C.; Qian, H.; Xu, B. Everolimus in hormone receptor-positive metastatic breast cancer: PIK3CA mutation H1047R was a potential efficacy biomarker in a retrospective study. BMC Cancer 2019, 19, 442. [Google Scholar] [CrossRef] [PubMed]
- Yu, K.; Toral-Barza, L.; Discafani, C.; Zhang, W.G.; Skotnicki, J.; Frost, P.; Gibbons, J.J. mTOR, a novel target in breast cancer: The effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr.-Relat. Cancer 2001, 8, 249–258. [Google Scholar] [CrossRef][Green Version]
- Wolff, A.C.; Lazar, A.A.; Bondarenko, I.; Garin, A.M.; Brincat, S.; Chow, L.; Sun, Y.; Neskovic-Konstantinovic, Z.; Guimaraes, R.C.; Fumoleau, P.; et al. Randomized phase III placebo-controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer. J. Clin. Oncol. 2013, 31, 195–202. [Google Scholar] [CrossRef][Green Version]
- Fleming, G.F.; Ma, C.X.; Huo, D.; Sattar, H.; Tretiakova, M.; Lin, L.; Hahn, O.M.; Olopade, F.O.; Nanda, R.; Hoffman, P.C.; et al. Phase II trial of temsirolimus in patients with metastatic breast cancer. Breast Cancer Res. Treat. 2012, 136, 355–363. [Google Scholar] [CrossRef][Green Version]
- Sadler, T.M.; Gavriil, M.; Annable, T.; Frost, P.; Greenberger, L.M.; Zhang, Y. Combination therapy for treating breast cancer using antiestrogen, ERA-923, and the mammalian target of rapamycin inhibitor, temsirolimus. Endocr.-Relat. Cancer 2006, 13, 863–873. [Google Scholar] [CrossRef][Green Version]
- Bhattacharvva, G.S.; Biswas, J.; Singh, J.K.; Singh, M.; Govindbabu, K.; Ranade, A.; Malhotra, H.; Parikh, P.; Shahid, T.; Basu, S. Reversal of tamoxifen resistance (hormone resistance) by addition of Sirolimus (mTOR Inhibitor) in metastatic breast cancer. Eur. J. Cancer 2011, 47, 9. [Google Scholar] [CrossRef]
- Seiler, M.; Ray-Coquard, I.; Melichar, B.; Yardley, D.A.; Wang, R.X.; Dodion, P.F.; Lee, M.A. Oral Ridaforolimus plus Trastuzumab for patients with HER2+ trastuzumab-refractory metastatic breast cancer. Clin. Breast Cancer 2015, 15, 60–65. [Google Scholar] [CrossRef] [PubMed]
- Shi, J.J.; Chen, S.M.; Guo, C.L.; Li, Y.X.; Ding, J.; Meng, L.H. The mTOR inhibitor AZD8055 overcomes tamoxifen resistance in breast cancer cells by down-regulating HSPB8. Acta Pharmacol. Sin. 2018, 39, 1338–1346. [Google Scholar] [CrossRef] [PubMed]
- Jordan, N.J.; Dutkowski, C.M.; Barrow, D.; Mottram, H.J.; Hutcheson, I.R.; Nicholson, R.I.; Guichard, S.M.; Gee, J.M.W. Impact of dual mTORC1/2 mTOR kinase inhibitor AZD8055 on acquired endocrine resistance in breast cancer in vitro. Breast Cancer Res. 2014, 23, R12. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Petrossian, K.; Nguyen, D.; Lo, C.; Kanaya, N.; Somlo, G.; Cui, Y.X.; Huang, C.-S.; Chen, S. Use of dual mTOR inhibitor MLN0128 against everolimus-resistant breast cancer. Breast Cancer Res. Treat. 2018, 170, 499–506. [Google Scholar] [CrossRef] [PubMed]
- Bostner, J.; Alayev, A.; Berman, A.Y.; Fornander, T.; Nordenskjöld, B.; Holz, M.K.; Stål, O. Raptor localization predicts prognosis and tamoxifen response in estrogen receptor-positive breast cancer. Breast Cancer Res. Treat. 2018, 168, 17–27. [Google Scholar] [CrossRef][Green Version]
- Zhu, L.; Li, X.; Shi, L.; Wu, J.; Qian, J.; Xia, T.; Zhou, W.-B.; Sun, X.; Xu-Jie, Z.; Wei, J.-F.; et al. Rapamycin enhances the sensitivity of ER‑positive breast cancer cells to tamoxifen by upregulating p73 expression. Oncol. Rep. 2019, 41, 455–464. [Google Scholar] [CrossRef][Green Version]
mTOR Inhibitors | Type of Breast Cancer | Type of Study | References |
---|---|---|---|
Everolimus + exemestane | hormone-receptor-positive advanced breast cancer | Phase 3, randomized trial | [180] |
Everolimus + fulvestrant | estrogen receptor-positive breast cancer | Phase 2 Manta trial | [181] |
Everolimus + tamoxifen | metastatic breast cancer | Phase II Randomized trial | [182] |
Everolimus + plustrastuzumab + vinorelbine | HER2-positive breast cancer | Phase 3 trial (Bolero-3) | [183] |
Everolimus + trastuzumab + paclitaxel | HER2-positive advanced breast cancer | Phase 2 multicenter study | [184] |
Everolimus | metastatic breast cancer | Retrospective study | [186] |
Temsirolimus + letrozole | hormone receptor-positive metastatic breast cancer | Phase III randomized trial | [188] |
Temsirolimus | metastatic breast cancer | Phase II trial | [189] |
Sirolimus + Tamoxifen | hormone receptor-positive and HER2-negative breast cancer | Phase I/II trial | [191] |
Ridaforolimus + trastuzumab | Human epidermal growth factor receptor 2–positive (HER2+) trastuzumab-refractory metastatic breast cancer | Phase IIb trail | [192] |
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Miricescu, D.; Totan, A.; Stanescu-Spinu, I.-I.; Badoiu, S.C.; Stefani, C.; Greabu, M. PI3K/AKT/mTOR Signaling Pathway in Breast Cancer: From Molecular Landscape to Clinical Aspects. Int. J. Mol. Sci. 2021, 22, 173. https://doi.org/10.3390/ijms22010173
Miricescu D, Totan A, Stanescu-Spinu I-I, Badoiu SC, Stefani C, Greabu M. PI3K/AKT/mTOR Signaling Pathway in Breast Cancer: From Molecular Landscape to Clinical Aspects. International Journal of Molecular Sciences. 2021; 22(1):173. https://doi.org/10.3390/ijms22010173
Chicago/Turabian StyleMiricescu, Daniela, Alexandra Totan, Iulia-Ioana Stanescu-Spinu, Silviu Constantin Badoiu, Constantin Stefani, and Maria Greabu. 2021. "PI3K/AKT/mTOR Signaling Pathway in Breast Cancer: From Molecular Landscape to Clinical Aspects" International Journal of Molecular Sciences 22, no. 1: 173. https://doi.org/10.3390/ijms22010173