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Breast Cancer

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31.10.2017 | Special Feature

Mechanism of resistance to endocrine therapy in breast cancer: the important role of PI3K/Akt/mTOR in estrogen receptor-positive, HER2-negative breast cancer

verfasst von: Kazuhiro Araki, Yasuo Miyoshi

Erschienen in: Breast Cancer | Ausgabe 4/2018

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Abstract

Endocrine therapy is a crucial treatment for estrogen receptor-positive (ER+) breast cancer, with proven clinical benefits. However, adaptive mechanisms emerge in the tumor, causing resistance to endocrine therapy. A better understanding of resistance mechanisms is needed to overcome this problem and to develop new, precise treatment strategies. Accumulating genetic and cancer biological studies demonstrate the importance of understanding the PI3K/Akt/mTOR and CDK4/6/RB pathways in ER+ HER2− breast cancer. PIK3CA (which encodes phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit α) is frequently mutated in breast cancer, and 30% of advanced ER+ HER2− breast cancers have an activating PIK3CA mutation. AKT1 mutations (E17K) have been found in 1.4–8% of breast cancer patients. ER+ breast cancer patients preferentially demonstrate gain of CCND1 (cyclin D1; 58% in luminal B vs. 29% in luminal A) and CDK4 (25% in luminal B vs. 14% in luminal A) and loss of CDKN2A (p16) and CDKN2C (p18), which are negatively regulated with the cell cycle and are correlated with the CDK4/6/RB pathway. Abnormalities in PI3K/Akt/mTOR and CDK4/6/RB pathways due to genetic alterations result in deregulated kinase activity and malignant transformation. This review focuses on the recent reports of the essential role of PI3K/Akt/mTOR and CDK4/6/RB pathways in ER+ HER2− breast cancer.

Ito Y, Miyashiro I, Ito H, Hosono S, Chihara D, Nakata-Yamada K, et al. Long-term survival and conditional survival of cancer patients in Japan using population-based cancer registry data. Cancer Sci. 2014;105:1480–6.CrossRefPubMedPubMedCentral

Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001;98:10869–74.CrossRefPubMedPubMedCentral

Coates AS, Winer EP, Goldhirsch A, Gelber RD, Gnant M, Piccart-Gebhart M, et al. Tailoring therapies–improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015. Ann Oncol. 2015;26:1533–46.CrossRefPubMedPubMedCentral

Early Breast Cancer Trialists’ Collaborative. G. Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet. 2015;386:1341–52.CrossRef

Wilson S, Chia SK. Treatment algorithms for hormone receptor-positive advanced breast cancer: applying the results from recent clinical trials into daily practice-insights, limitations, and moving forward. Am Soc Clin Oncol Educ Book. 2013;2013:20–7.CrossRef

Baselga J, Im SA, Iwata H, Cortes J, De Laurentiis M, Jiang Z, et al. Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18:904–16.CrossRefPubMedPubMedCentral

Krop IE, Mayer IA, Ganju V, Dickler M, Johnston S, Morales S, et al. Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2016;17:811–21.CrossRefPubMedPubMedCentral

Schmid P, Pinder SE, Wheatley D, Macaskill J, Zammit C, Hu J, et al. Phase II randomized preoperative window-of-opportunity study of the PI3K Inhibitor Pictilisib Plus Anastrozole compared with Anastrozole alone in patients with estrogen receptor-positive breast cancer. J Clin Oncol. 2016;34:1987–94.CrossRefPubMedPubMedCentral

Patnaik A, Appleman LJ, Tolcher AW, Papadopoulos KP, Beeram M, Rasco DW, et al. First-in-human phase I study of copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin’s lymphomas. Ann Oncol. 2016;27:1928–40.CrossRefPubMedPubMedCentral

10.

Mayer IA, Abramson VG, Formisano L, Balko JM, Estrada MV, Sanders ME, et al. A phase Ib study of Alpelisib (BYL719), a PI3Kalpha-specific inhibitor, with Letrozole in ER+/HER2− metastatic breast cancer. Clin Cancer Res. 2017;23:26–34.CrossRefPubMed

11.

Juric D, Krop I, Ramanathan RK, Wilson TR, Ware JA, Sanabria Bohorquez SM, et al. Phase I dose-escalation study of Taselisib, an oral PI3K inhibitor, in patients with advanced solid tumors. Cancer Discov. 2017;7:704–15.CrossRefPubMedPubMedCentral

12.

Saura C, Roda D, Rosello S, Oliveira M, Macarulla T, Perez-Fidalgo JA, et al. A first-in-human phase I study of the ATP-competitive AKT inhibitor Ipatasertib demonstrates robust and safe targeting of AKT in patients with solid tumors. Cancer Discov. 2017;7:102–13.CrossRefPubMed

13.

Kim SB, Dent R, Im SA, Espie M, Blau S, Tan AR, et al. Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2017;18:1360–72.CrossRefPubMedPubMedCentral

14.

Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366:520–9.CrossRefPubMed

15.

Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, et al. Palbociclib and Letrozole in advanced breast cancer. N Engl J Med. 2016;375:1925–36.CrossRefPubMed

16.

Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med. 2016;375:1738–48.CrossRefPubMed

17.

Sledge GW Jr, Toi M, Neven P, Sohn J, Inoue K, Pivot X, et al. MONARCH 2: Abemaciclib in combination with Fulvestrant in women with HR+/HER2− advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017;35:2875–84.CrossRefPubMed

18.

LoRusso PM. Inhibition of the PI3K/AKT/mTOR pathway in solid tumors. J Clin Oncol. 2016;34:3803–15.CrossRefPubMedPubMedCentral

19.

Whitman M, Downes CP, Keeler M, Keller T, Cantley L. Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate. Nature. 1988;332:644–6.CrossRefPubMed

20.

Cantley LC. The phosphoinositide 3-kinase pathway. Science. 2002;296:1655–7.CrossRefPubMed

21.

Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD. Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol. 2001;17:615–75.CrossRefPubMed

22.

Crackower MA, Oudit GY, Kozieradzki I, Sarao R, Sun H, Sasaki T, et al. Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell. 2002;110:737–49.CrossRefPubMed

23.

Yang ZZ, Tschopp O, Baudry A, Dummler B, Hynx D, Hemmings BA. Physiological functions of protein kinase B/Akt. Biochem Soc Trans. 2004;32:350–4.CrossRefPubMed

24.

Kurosu H, Maehama T, Okada T, Yamamoto T, Hoshino S, Fukui Y, et al. Heterodimeric phosphoinositide 3-kinase consisting of p85 and p110beta is synergistically activated by the betagamma subunits of G proteins and phosphotyrosyl peptide. J Biol Chem. 1997;272:24252–6.CrossRefPubMed

25.

Roche S, Downward J, Raynal P, Courtneidge SA. A function for phosphatidylinositol 3-kinase beta (p85alpha-p110beta) in fibroblasts during mitogenesis: requirement for insulin- and lysophosphatidic acid-mediated signal transduction. Mol Cell Biol. 1998;18:7119–29.CrossRefPubMedPubMedCentral

26.

Engelman JA. Targeting PI3K signaling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009;9:550–62.CrossRefPubMed

27.

Yu J, Wjasow C, Backer JM. Regulation of the p85/p110alpha phosphatidylinositol 3′-kinase. Distinct roles for the n-terminal and c-terminal SH2 domains. J Biol Chem. 1998;273:30199–203.CrossRefPubMed

28.

Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307:1098–101.CrossRefPubMed

29.

Luo J, Manning BD, Cantley LC. Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell. 2003;4:257–62.CrossRefPubMed

30.

Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet. 2006;7:606–19.CrossRefPubMed

31.

Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signaling controls tumor cell growth. Nature. 2006;441:424–30.CrossRefPubMed

32.

Bader AG, Kang S, Zhao L, Vogt PK. Oncogenic PI3K deregulates transcription and translation. Nat Rev Cancer. 2005;5:921–9.CrossRefPubMed

33.

Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129:1261–74.CrossRefPubMedPubMedCentral

34.

Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33.CrossRefPubMedPubMedCentral

35.

Turner NC, Neven P, Loibl S, Andre F. Advances in the treatment of advanced oestrogen-receptor-positive breast cancer. Lancet. 2017;389:2403–14.CrossRefPubMed

36.

Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumors. Nature. 2012;490:61–70.CrossRef

37.

Lehmann BD, Bauer JA, Schafer JM, Pendleton CS, Tang L, Johnson KC, 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;16:406.CrossRefPubMedPubMedCentral

38.

Samuels Y, Velculescu VE. Oncogenic mutations of PIK3CA in human cancers. Cell Cycle. 2004;3:1221–4.CrossRefPubMed

39.

Van Keymeulen A, Lee MY, Ousset M, Brohee S, Rorive S, Giraddi RR, et al. Reactivation of multipotency by oncogenic PIK3CA induces breast tumour heterogeneity. Nature. 2015;525:119–23.CrossRefPubMed

40.

Lawson DA, Bhakta NR, Kessenbrock K, Prummel KD, Yu Y, Takai K, et al. Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells. Nature. 2015;526:131–5.CrossRefPubMedPubMedCentral

41.

Bosch A, Li Z, Bergamaschi A, Ellis H, Toska E, Prat A, et al. PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer. Sci Transl Med. 2015;7:283ra51.

42.

Osborne CK, Shou J, Massarweh S, Schiff R. Crosstalk between estrogen receptor and growth factor receptor pathways as a cause for endocrine therapy resistance in breast cancer. Clin Cancer Res. 2005;11:865s–70s.PubMed

43.

Osborne CK, Neven P, Dirix LY, Mackey JR, Robert J, Underhill C, et al. Gefitinib or placebo in combination with tamoxifen in patients with hormone receptor-positive metastatic breast cancer: a randomized phase II study. Clin Cancer Res. 2011;17:1147–59.CrossRefPubMedPubMedCentral

44.

Robertson JF, Ferrero JM, Bourgeois H, Kennecke H, de Boer RH, Jacot W, et al. Ganitumab with either exemestane or fulvestrant for postmenopausal women with advanced, hormone-receptor-positive breast cancer: a randomised, controlled, double-blind, phase 2 trial. Lancet Oncol. 2013;14:228–35.CrossRefPubMed

45.

Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997;275:1943–7.CrossRefPubMed

46.

Bostrom J, Cobbers JM, Wolter M, Tabatabai G, Weber RG, Lichter P, et al. Mutation of the PTEN (MMAC1) tumor suppressor gene in a subset of glioblastomas but not in meningiomas with loss of chromosome arm 10q. Cancer Res. 1998;58:29–33.PubMed

47.

Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 1998;273:13375–8.CrossRefPubMed

48.

Maehama T, Dixon JE. PTEN: a tumour suppressor that functions as a phospholipid phosphatase. Trends Cell Biol. 1999;9:125–8.CrossRefPubMed

49.

Sansal I, Sellers WR. The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol. 2004;22:2954–63.CrossRefPubMed

50.

Stommel JM, Kimmelman AC, Ying H, Nabioullin R, Ponugoti AH, Wiedemeyer R, et al. Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science. 2007;318:287–90.CrossRefPubMed

51.

Bianco R, Shin I, Ritter CA, Yakes FM, Basso A, Rosen N, et al. Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. Oncogene. 2003;22:2812–22.CrossRefPubMed

52.

Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell. 2007;12:395–402.CrossRefPubMed

53.

Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 2004;6:117–27.CrossRefPubMed

54.

Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304:554.CrossRefPubMed

55.

Perez-Tenorio G, Alkhori L, Olsson B, Waltersson MA, Nordenskjold B, Rutqvist LE, et al. PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer. Clin Cancer Res. 2007;13:3577–84.CrossRefPubMed

56.

Ellis MJ, Lin L, Crowder R, Tao Y, Hoog J, Snider J, et al. Phosphatidyl-inositol-3-kinase alpha catalytic subunit mutation and response to neoadjuvant endocrine therapy for estrogen receptor positive breast cancer. Breast Cancer Res Treat. 2010;119:379–90.CrossRefPubMedPubMedCentral

57.

Zhao JJ, Liu Z, Wang L, Shin E, Loda MF, Roberts TM. The oncogenic properties of mutant p110alpha and p110beta phosphatidylinositol 3-kinases in human mammary epithelial cells. Proc Natl Acad Sci USA. 2005;102:18443–8.CrossRefPubMedPubMedCentral

58.

Isakoff SJ, Engelman JA, Irie HY, Luo J, Brachmann SM, Pearline RV, et al. Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. Cancer Res. 2005;65:10992–1000.CrossRefPubMed

59.

Miled N, Yan Y, Hon WC, Perisic O, Zvelebil M, Inbar Y, et al. Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science. 2007;317:239–42.CrossRefPubMed

60.

Huang CH, Mandelker D, Schmidt-Kittler O, Samuels Y, Velculescu VE, Kinzler KW, et al. The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations. Science. 2007;318:1744–8.CrossRefPubMed

61.

Mukohara T. PI3K mutations in breast cancer: prognostic and therapeutic implications. Breast Cancer (Dove Med Press). 2015;7:111–23.PubMedPubMedCentral

62.

Zhao L, Vogt PK. Helical domain and kinase domain mutations in p110alpha of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proc Natl Acad Sci U S A. 2008;105:2652–7.CrossRefPubMedPubMedCentral

63.

Dunlap J, Le C, Shukla A, Patterson J, Presnell A, Heinrich MC, et al. Phosphatidylinositol-3-kinase and AKT1 mutations occur early in breast carcinoma. Breast Cancer Res Treat. 2010;120:409–18.CrossRefPubMed

64.

Beelen K, Opdam M, Severson TM, Koornstra RH, Vincent AD, Wesseling J, et al. PIK3CA mutations, phosphatase and tensin homolog, human epidermal growth factor receptor 2, and insulin-like growth factor 1 receptor and adjuvant tamoxifen resistance in postmenopausal breast cancer patients. Breast Cancer Res. 2014;16:R13.CrossRefPubMedPubMedCentral

65.

Ramirez-Ardila DE, Helmijr JC, Look MP, Lurkin I, Ruigrok-Ritstier K, van Laere S, et al. Hotspot mutations in PIK3CA associate with first-line treatment outcome for aromatase inhibitors but not for tamoxifen. Breast Cancer Res Treat. 2013;139:39–49.CrossRefPubMed

66.

Miller TW, Balko JM, Fox EM, Ghazoui Z, Dunbier A, Anderson H, et al. ERalpha-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer. Cancer Discov. 2011;1:338–51.CrossRefPubMedPubMedCentral

67.

Sanchez CG, Ma CX, Crowder RJ, Guintoli T, Phommaly C, Gao F, et al. Preclinical modeling of combined phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen receptor-positive breast cancer. Breast Cancer Res. 2011;13:R21.CrossRefPubMedPubMedCentral

68.

Crowder RJ, Phommaly C, Tao Y, Hoog J, Luo J, Perou CM, et al. PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer. Cancer Res. 2009;69:3955–62.CrossRefPubMedPubMedCentral

69.

Cizkova M, Vacher S, Meseure D, Trassard M, Susini A, Mlcuchova D, et al. PIK3R1 underexpression is an independent prognostic marker in breast cancer. BMC Cancer. 2013;13:545.CrossRefPubMedPubMedCentral

70.

Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, Neve RM, Kuo WL, Davies M, et al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res. 2008;68:6084–91.CrossRefPubMedPubMedCentral

71.

Carpten JD, Faber AL, Horn C, Donoho GP, Briggs SL, Robbins CM, et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature. 2007;448:439–44.CrossRefPubMed

72.

Perez-Tenorio G, Stal O. Southeast Sweden Breast Cancer G. Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients. Br J Cancer. 2002;86:540–5.CrossRefPubMedPubMedCentral

73.

Tokunaga E, Kimura Y, Mashino K, Oki E, Kataoka A, Ohno S, et al. Activation of PI3K/Akt signaling and hormone resistance in breast cancer. Breast Cancer. 2006;13:137–44.CrossRefPubMed

74.

deGraffenried LA, Friedrichs WE, Russell DH, Donzis EJ, Middleton AK, Silva JM, et al. Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt Activity. Clin Cancer Res. 2004;10:8059–67.

75.

Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer. 2006;6:729–34.CrossRefPubMed

76.

Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149:274–93.CrossRefPubMedPubMedCentral

77.

LoRusso PM. Mammalian target of rapamycin as a rational therapeutic target for breast cancer treatment. Oncology. 2013;84:43–56.CrossRefPubMed

78.

McAuliffe PF, Meric-Bernstam F, Mills GB, Gonzalez-Angulo AM. Deciphering the role of PI3K/Akt/mTOR pathway in breast cancer biology and pathogenesis. Clin Breast Cancer. 2010;10(Suppl 3):S59–65.CrossRefPubMed

79.

Sheri A, Martin LA, Johnston S. Targeting endocrine resistance: is there a role for mTOR inhibition? Clin Breast Cancer. 2010;10(Suppl 3):S79–85.CrossRefPubMed

80.

Yip CK, Murata K, Walz T, Sabatini DM, Kang SA. Structure of the human mTOR complex I and its implications for rapamycin inhibition. Mol Cell. 2010;38:768–74.CrossRefPubMedPubMedCentral

81.

Yang Z, Klionsky DJ. Eaten alive: a history of macroautophagy. Nat Cell Biol. 2010;12:814–22.CrossRefPubMedPubMedCentral

82.

Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003;115:577–90.CrossRefPubMed

83.

Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA, et al. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci USA. 2004;101:3329–35.CrossRefPubMedPubMedCentral

84.

Borders EB, Bivona C, Medina PJ. Mammalian target of rapamycin: biological function and target for novel anticancer agents. Am J Health Syst Pharm. 2010;67:2095–106.CrossRefPubMed

85.

Miller TW, Hennessy BT, Gonzalez-Angulo AM, Fox EM, Mills GB, Chen H, et al. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Invest. 2010;120:2406–13.CrossRefPubMedPubMedCentral

86.

Akcakanat A, Sahin A, Shaye AN, Velasco MA, Meric-Bernstam F. Comparison of Akt/mTOR signaling in primary breast tumors and matched distant metastases. Cancer. 2008;112:2352–8.CrossRefPubMed

87.

Boulay A, Rudloff J, Ye J, Zumstein-Mecker S, O’Reilly T, Evans DB, et al. Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer. Clin Cancer Res. 2005;11:5319–28.CrossRefPubMed

88.

Margariti N, Fox SB, Bottini A, Generali D. “Overcoming breast cancer drug resistance with mTOR inhibitors”. Could it be a myth or a real possibility in the short-term future? Breast Cancer Res Treat. 2011;128:599–606.CrossRefPubMed

89.

Kim EK, Kim HA, Koh JS, Kim MS, Kim KI, Lee JI, et al. Phosphorylated S6K1 is a possible marker for endocrine therapy resistance in hormone receptor-positive breast cancer. Breast Cancer Res Treat. 2011;126:93–9.CrossRefPubMed

90.

Piccart M, Hortobagyi GN, Campone M, Pritchard KI, Lebrun F, Ito Y, et al. Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2dagger. Ann Oncol. 2014;25:2357–62.CrossRefPubMedPubMedCentral

91.

Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, 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;30:2718–24.CrossRefPubMed

92.

Mayer IA, Dent R, Tan T, Savas P, Loi S. Novel targeted agents and immunotherapy in breast cancer. Am Soc Clin Oncol Educ Book. 2017;37:65–75.CrossRefPubMed

93.

Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009;9:153–66.CrossRefPubMed

94.

Anders L, Ke N, Hydbring P, Choi YJ, Widlund HR, Chick JM, et al. A systematic screen for CDK4/6 substrates links FOXM1 phosphorylation to senescence suppression in cancer cells. Cancer Cell. 2011;20:620–34.CrossRefPubMedPubMedCentral

95.

Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.CrossRefPubMed

96.

Butt AJ, McNeil CM, Musgrove EA, Sutherland RL. Downstream targets of growth factor and oestrogen signalling and endocrine resistance: the potential roles of c-Myc, cyclin D1 and cyclin E. Endocr Relat Cancer. 2005;12(Suppl 1):S47–59.CrossRefPubMed

97.

Thangavel C, Dean JL, Ertel A, Knudsen KE, Aldaz CM, Witkiewicz AK, et al. Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. Endocr Relat Cancer. 2011;18:333–45.CrossRefPubMedPubMedCentral

98.

Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 2009;11:R77.CrossRefPubMedPubMedCentral

Titel: Mechanism of resistance to endocrine therapy in breast cancer: the important role of PI3K/Akt/mTOR in estrogen receptor-positive, HER2-negative breast cancer
verfasst von: Kazuhiro Araki
Yasuo Miyoshi
Publikationsdatum: 31.10.2017
Verlag: Springer Japan
Erschienen in: Breast Cancer / Ausgabe 4/2018
Print ISSN: 1340-6868
Elektronische ISSN: 1880-4233
DOI: https://doi.org/10.1007/s12282-017-0812-x

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Mechanism of resistance to endocrine therapy in breast cancer: the important role of PI3K/Akt/mTOR in estrogen receptor-positive, HER2-negative breast cancer

Abstract

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