Mechanisms associated with resistance to tamoxifen in estrogen receptor-positive breast cancer (Review)

Viedma-Rodríguez,Rubí; Baiza-Gutman,Luis; Salamanca‑Gómez,Fabio; Diaz‑Zaragoza,Mariana; Martínez-Hernández,Guadalupe; Ruiz Esparza‑Garrido,Ruth; Velázquez-Flores,Miguel Angel; Arenas-Aranda,Diego

doi:10.3892/or.2014.3190

Mechanisms associated with resistance to tamoxifen in estrogen receptor-positive breast cancer (Review)

Authors:
- Rubí Viedma-Rodríguez
- Luis Baiza-Gutman
- Fabio Salamanca‑Gómez
- Mariana Diaz‑Zaragoza
- Guadalupe Martínez-Hernández
- Ruth Ruiz Esparza‑Garrido
- Miguel Angel Velázquez-Flores
- Diego Arenas-Aranda
View Affiliations

Affiliations: Molecular Genetics Laboratory, Medical Research Unit in Human Genetics, Pediatric Hospital, National Medical Center Century XXI (CMN-SXXI), Mexican Social Security Institute (IMSS), Mexico City, Mexico, Unit of Morphology and Function, Faculty of Higher Studies (FES) Iztacala, National Autonomous University of Mexico (UNAM), Los Reyes Iztacala, State of Mexico, Mexico, Biomedical Research Institute (IIBM), UNAM, Mexico City, Mexico
Published online on: May 16, 2014 https://doi.org/10.3892/or.2014.3190
Pages: 3-15

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Anti-estrogens such as tamoxifen are widely used in the clinic to treat estrogen receptor-positive breast tumors. Patients with estrogen receptor-positive breast cancer initially respond to treatment with anti-hormonal agents such as tamoxifen, but remissions are often followed by the acquisition of resistance and, ultimately, disease relapse. The development of a rationale for the effective treatment of tamoxifen-resistant breast cancer requires an understanding of the complex signal transduction mechanisms. In the present study, we explored some mechanisms associated with resistance to tamoxifen, such as pharmacologic mechanisms, loss or modification in estrogen receptor expression, alterations in co-regulatory proteins and the regulation of the different signaling pathways that participate in different cellular processes such as survival, proliferation, stress, cell cycle, inhibition of apoptosis regulated by the Bcl-2 family, autophagy, altered expression of microRNA, and signaling pathways that regulate the epithelial-mesenchymal transition in the tumor microenvironment. Delineation of the molecular mechanisms underlying the development of resistance may aid in the development of treatment strategies to enhance response and compromise resistance.

View Figures

View References

1	Kohn AD and Moon RT: Wnt and calcium signaling: β-catenin-independent pathways. Cell Calcium. 38:439–446. 2005.
2	Deroo BJ and Korach KS: Estrogen receptors and human disease. J Clin Invest. 116:561–570. 2006. View Article : Google Scholar : PubMed/NCBI
3	Riggins RB, Schrecengost RS, Guerrero MS and Bouton AH: Pathways to tamoxifen resistance. Cancer Lett. 256:1–24. 2007. View Article : Google Scholar : PubMed/NCBI
4	Mueller SO and Korach KS: Estrogen receptors and endocrine diseases: lessons from estrogen receptor knockout mice. Curr Opin Pharmacol. 1:613–619. 2001. View Article : Google Scholar : PubMed/NCBI
5	Henderson BE and Feigelson HS: Hormonal carcinogenesis. Carcinogenesis. 21:427–433. 2000. View Article : Google Scholar : PubMed/NCBI
6	Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S and Gustafsson JA: Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA. 93:5925–5930. 1996. View Article : Google Scholar : PubMed/NCBI
7	Mosselman S, Polman J and Dijkema R: ERβ: identification and characterization of a novel human estrogen receptor. FEBS Lett. 392:49–53. 1996.
8	Dixon D, Couse JF and Korach KS: Disruption of the estrogen receptor gene in mice. Toxicol Pathol. 25:518–520. 1997. View Article : Google Scholar : PubMed/NCBI
9	Elliston JF, Fawell SE, Klein-Hitpass L, et al: Mechanism of estrogen receptor-dependent transcription in a cell-free system. Mol Cell Biol. 10:6607–6612. 1990.PubMed/NCBI
10	Frasor J, Danes JM, Komm B, Chang KC, Lyttle CR and Katzenellenbogen BS: Profiling of estrogen up- and down-regulated gene expression in human breast cancer cells: insights into gene networks and pathways underlying estrogenic control of proliferation and cell phenotype. Endocrinology. 144:4562–4574. 2003. View Article : Google Scholar : PubMed/NCBI
11	Webb P, Lopez GN, Uht RM and Kushner PJ: Tamoxifen activation of the estrogen receptor/AP-1 pathway: potential origin for the cell-specific estrogen-like effects of antiestrogens. Mol Endocrinol. 9:443–456. 1995.PubMed/NCBI
12	Kushner PJ, Agard DA, Greene GL, et al: Estrogen receptor pathways to AP-1. J Steroid Biochem Mol Biol. 74:311–317. 2000. View Article : Google Scholar : PubMed/NCBI
13	Smith CL and O’Malley BW: Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr Rev. 25:45–71. 2004. View Article : Google Scholar : PubMed/NCBI
14	Osborne CK, Bardou V, Hopp TA, et al: Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer. J Natl Cancer Inst. 95:353–361. 2003. View Article : Google Scholar : PubMed/NCBI
15	Saville B, Wormke M, Wang F, et al: Ligand-, cell-, and estrogen receptor subtype (α/β)-dependent activation at GC-rich (Sp1) promoter elements. J Biol Chem. 275:5379–5387. 2000.
16	Kelloff GJ, Lippman SM, Dannenberg AJ, et al: Progress in chemoprevention drug development: the promise of molecular biomarkers for prevention of intraepithelial neoplasia and cancer - a plan to move forward. Clin Cancer Res. 12:3661–3697. 2006. View Article : Google Scholar : PubMed/NCBI
17	Schiff R, Massarweh SA, Shou J, Bharwani L, Mohsin SK and Osborne CK: Cross-talk between estrogen receptor and growth factor pathways as a molecular target for overcoming endocrine resistance. Clin Cancer Res. 10:331S–336S. 2004. View Article : Google Scholar : PubMed/NCBI
18	Le Goff P, Montano MM, Schodin DJ and Katzenellenbogen BS: Phosphorylation of the human estrogen receptor. Identification of hormone-regulated sites and examination of their influence on transcriptional activity. J Biol Chem. 269:4458–4466. 1994.PubMed/NCBI
19	Vyhlidal C, Samudio I, Kladde MP and Safe S: Transcriptional activation of transforming growth factor α by estradiol: requirement for both a GC-rich site and an estrogen response element half-site. J Mol Endocrinol. 24:329–338. 2000.
20	Lee AV, Cui X and Oesterreich S: Cross-talk among estrogen receptor, epidermal growth factor, and insulin-like growth factor signaling in breast cancer. Clin Cancer Res. 7(Suppl 12): S4429–S4435. 2001.PubMed/NCBI
21	Yarden RI, Wilson MA and Chrysogelos SA: Estrogen suppression of EGFR expression in breast cancer cells: a possible mechanism to modulate growth. J Cell Biochem. (Suppl 36): 232–246. 2001. View Article : Google Scholar : PubMed/NCBI
22	Bayliss J, Hilger A, Vishnu P, Diehl K and El-Ashry D: Reversal of the estrogen receptor negative phenotype in breast cancer and restoration of antiestrogen response. Clin Cancer Res. 13:7029–7036. 2007. View Article : Google Scholar : PubMed/NCBI
23	Cui X, Zhang P, Deng W, et al: Insulin-like growth factor-I inhibits progesterone receptor expression in breast cancer cells via the phosphatidylinositol 3–kinase/Akt/mammalian target of rapamycin pathway: progesterone receptor as a potential indicator of growth factor activity in breast cancer. Mol Endocrinol. 17:575–588. 2003.PubMed/NCBI
24	Brinkman JA and El-Ashry D: ER re-expression and re-sensitization to endocrine therapies in ER-negative breast cancers. J Mammary Gland Biol Neoplasia. 14:67–78. 2009. View Article : Google Scholar : PubMed/NCBI
25	Levin ER and Pietras RJ: Estrogen receptors outside the nucleus in breast cancer. Breast Cancer Res Treat. 108:351–361. 2008. View Article : Google Scholar : PubMed/NCBI
26	Pedram A, Razandi M, Lubahn D, Liu J, Vannan M and Levin ER: Estrogen inhibits cardiac hypertrophy: role of estrogen receptor-β to inhibit calcineurin. Endocrinology. 149:3361–3369. 2008.PubMed/NCBI
27	Wu RC, Qin J, Yi P, et al: Selective phosphorylations of the SRC-3/AIB1 coactivator integrate genomic reponses to multiple cellular signaling pathways. Mol Cell. 15:937–949. 2004. View Article : Google Scholar : PubMed/NCBI
28	Pontiggia O, Rodriguez V, Fabris V, et al: Establishment of an in vitro estrogen-dependent mouse mammary tumor model: a new tool to understand estrogen responsiveness and development of tamoxifen resistance in the context of stromal-epithelial interactions. Breast Cancer Res Treat. 116:247–255. 2009. View Article : Google Scholar
29	Machuca TN, Hsin MK, Ott HC, et al: Injury-specific ex vivo treatment of the donor lung: pulmonary thrombolysis followed by successful lung transplantation. Am J Respir Crit Care Med. 188:878–880. 2013. View Article : Google Scholar : PubMed/NCBI
30	Goetz MP, Rae JM, Suman VJ, et al: Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol. 23:9312–9318. 2005. View Article : Google Scholar : PubMed/NCBI
31	Stearns V and Rae JM: Pharmacogenetics and breast cancer endocrine therapy: CYP2D6 as a predictive factor for tamoxifen metabolism and drug response? Expert Rev Mol Med. 10:e342008. View Article : Google Scholar : PubMed/NCBI
32	Jaiswal BS, Janakiraman V, Kljavin NM, et al: Somatic mutations in p85α promote tumorigenesis through class IA PI3K activation. Cancer Cell. 16:463–474. 2009.
33	Madeira M, Mattar A, Logullo AF, Soares FA and Gebrim LH: Estrogen receptor alpha/beta ratio and estrogen receptor beta as predictors of endocrine therapy responsiveness-a randomized neoadjuvant trial comparison between anastrozole and tamoxifen for the treatment of postmenopausal breast cancer. BMC Cancer. 13:4252013. View Article : Google Scholar
34	McGuire WL: Current status of estrogen receptors in human breast cancer. Cancer. 36:638–644. 1975. View Article : Google Scholar : PubMed/NCBI
35	Esslimani-Sahla M, Simony-Lafontaine J, Kramar A, et al: Estrogen receptor β (ERβ) level but not its ERβcx variant helps to predict tamoxifen resistance in breast cancer. Clin Cancer Res. 10:5769–5776. 2004.
36	Hopp TA, Weiss HL, Parra IS, Cui Y, Osborne CK and Fuqua SA: Low levels of estrogen receptor β protein predict resistance to tamoxifen therapy in breast cancer. Clin Cancer Res. 10:7490–7499. 2004.
37	Kuiper GG, Lemmen JG, Carlsson B, et al: Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor β. Endocrinology. 139:4252–4263. 1998.
38	Yang X, Phillips DL, Ferguson AT, Nelson WG, Herman JG and Davidson NE: Synergistic activation of functional estrogen receptor (ER)-α by DNA methyltransferase and histone deacetylase inhibition in human ER-α-negative breast cancer cells. Cancer Res. 61:7025–7029. 2001.
39	Parl FF: Multiple mechanisms of estrogen receptor gene repression contribute to ER-negative breast cancer. Pharmacogenomics J. 3:251–253. 2003. View Article : Google Scholar : PubMed/NCBI
40	Ottaviano YL, Issa JP, Parl FF, Smith HS, Baylin SB and Davidson NE: Methylation of the estrogen receptor gene CpG island marks loss of estrogen receptor expression in human breast cancer cells. Cancer Res. 54:2552–2555. 1994.PubMed/NCBI
41	Robertson KD, Ait-Si-Ali S, Yokochi T, Wade PA, Jones PL and Wolffe AP: DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nat Genet. 25:338–342. 2000. View Article : Google Scholar : PubMed/NCBI
42	Fan J, Yin WJ, Lu JS, et al: ERα negative breast cancer cells restore response to endocrine therapy by combination treatment with both HDAC inhibitor and DNMT inhibitor. J Cancer Res Clin Oncol. 134:883–890. 2008.
43	Zhou Q, Shaw PG and Davidson NE: Inhibition of histone deacetylase suppresses EGF signaling pathways by destabilizing EGFR mRNA in ER-negative human breast cancer cells. Breast Cancer Res Treat. 117:443–451. 2009. View Article : Google Scholar : PubMed/NCBI
44	Sabnis GJ, Goloubeva O, Chumsri S, Nguyen N, Sukumar S and Brodie AM: Functional activation of the estrogen receptor-α and aromatase by the HDAC inhibitor entinostat sensitizes ER-negative tumors to letrozole. Cancer Res. 71:1893–1903. 2011.
45	Mahfoudi A, Roulet E, Dauvois S, Parker MG and Wahli W: Specific mutations in the estrogen receptor change the properties of antiestrogens to full agonists. Proc Natl Acad Sci USA. 92:4206–4210. 1995. View Article : Google Scholar : PubMed/NCBI
46	Wolf DM and Jordan VC: The estrogen receptor from a tamoxifen stimulated MCF-7 tumor variant contains a point mutation in the ligand binding domain. Breast Cancer Res Treat. 31:129–138. 1994. View Article : Google Scholar : PubMed/NCBI
47	MacGregor Schafer J, Liu H, Bentrem DJ, Zapf JW and Jordan VC: Allosteric silencing of activating function 1 in the 4-hydroxytamoxifen estrogen receptor complex is induced by substituting glycine for aspartate at amino acid 351. Cancer Res. 60:5097–5105. 2000.
48	Thomas RS, Sarwar N, Phoenix F, Coombes RC and Ali S: Phosphorylation at serines 104 and 106 by Erk1/2 MAPK is important for estrogen receptor-α activity. J Mol Endocrinol. 40:173–184. 2008.PubMed/NCBI
49	Chen D, Washbrook E, Sarwar N, et al: Phosphorylation of human estrogen receptor α at serine 118 by two distinct signal transduction pathways revealed by phosphorylation-specific antisera. Oncogene. 21:4921–4931. 2002.
50	Williams CC, Basu A, El-Gharbawy A, Carrier LM, Smith CL and Rowan BG: Identification of four novel phosphorylation sites in estrogen receptor α: impact on receptor-dependent gene expression and phosphorylation by protein kinase CK2. BMC Biochem. 10:362009.PubMed/NCBI
51	Rogatsky I, Trowbridge JM and Garabedian MJ: Potentiation of human estrogen receptor α transcriptional activation through phosphorylation of serines 104 and 106 by the cyclin A-CDK2 complex. J Biol Chem. 274:22296–22302. 1999.
52	Michalides R, van Tinteren H, Balkenende A, et al: Cyclin A is a prognostic indicator in early stage breast cancer with and without tamoxifen treatment. Br J Cancer. 86:402–408. 2002. View Article : Google Scholar : PubMed/NCBI
53	Vendrell JA, Bieche I, Desmetz C, et al: Molecular changes associated with the agonist activity of hydroxy-tamoxifen and the hyper-response to estradiol in hydroxy-tamoxifen-resistant breast cancer cell lines. Endocr Relat Cancer. 12:75–92. 2005. View Article : Google Scholar
54	Likhite VS, Stossi F, Kim K, Katzenellenbogen BS and Katzenellenbogen JA: Kinase-specific phosphorylation of the estrogen receptor changes receptor interactions with ligand, deoxyribonucleic acid, and coregulators associated with alterations in estrogen and tamoxifen activity. Mol Endocrinol. 20:3120–3132. 2006. View Article : Google Scholar
55	Kato S, Endoh H, Masuhiro Y, et al: Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science. 270:1491–1494. 1995. View Article : Google Scholar : PubMed/NCBI
56	Barone I, Brusco L and Fuqua SA: Estrogen receptor mutations and changes in downstream gene expression and signaling. Clin Cancer Res. 16:2702–2708. 2010. View Article : Google Scholar : PubMed/NCBI
57	de Leeuw R, Neefjes J and Michalides R: A role for estrogen receptor phosphorylation in the resistance to tamoxifen. Int J Breast Cancer. 2011:2324352011.PubMed/NCBI
58	Osborne CK and Schiff R: Estrogen-receptor biology: continuing progress and therapeutic implications. J Clin Oncol. 23:1616–1622. 2005. View Article : Google Scholar : PubMed/NCBI
59	Girault I, Bièche I and Lidereau R: Role of estrogen receptor α transcriptional coregulators in tamoxifen resistance in breast cancer. Maturitas. 54:342–351. 2006.
60	Webb P, Nguyen P, Shinsako J, et al: Estrogen receptor activation function 1 works by binding p160 coactivator proteins. Mol Endocrinol. 12:1605–1618. 1998. View Article : Google Scholar : PubMed/NCBI
61	Kressler D, Hock MB and Kralli A: Coactivators PGC-1β and SRC-1 interact functionally to promote the agonist activity of the selective estrogen receptor modulator tamoxifen. J Biol Chem. 282:26897–26907. 2007.
62	Fuqua SA, Schiff R, Parra I, et al: Estrogen receptor β protein in human breast cancer: correlation with clinical tumor parameters. Cancer Res. 63:2434–2439. 2003.
63	Lavinsky RM, Jepsen K, Heinzel T, et al: Diverse signaling pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes. Proc Natl Acad Sci USA. 95:2920–2925. 1998. View Article : Google Scholar : PubMed/NCBI
64	Kurokawa H, Lenferink AE, Simpson JF, et al: Inhibition of HER2/neu (erbB-2) and mitogen-activated protein kinases enhances tamoxifen action against HER2-overexpressing, tamoxifen-resistant breast cancer cells. Cancer Res. 60:5887–5894. 2000.
65	Massarweh S, Osborne CK, Creighton CJ, et al: Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function. Cancer Res. 68:826–833. 2008. View Article : Google Scholar : PubMed/NCBI
66	Fagan DH, Uselman RR, Sachdev D and Yee D: Acquired resistance to tamoxifen is associated with loss of the type I insulin-like growth factor receptor: implications for breast cancer treatment. Cancer Res. 72:3372–3380. 2012. View Article : Google Scholar : PubMed/NCBI
67	Ciampolillo A, De Tullio C and Giorgino F: The IGF-I/IGF-I receptor pathway: implications in the pathophysiology of thyroid cancer. Curr Med Chem. 12:2881–2891. 2005. View Article : Google Scholar : PubMed/NCBI
68	Lee AV, Weng CN, Jackson JG and Yee D: Activation of estrogen receptor-mediated gene transcription by IGF-I in human breast cancer cells. J Endocrinol. 152:39–47. 1997. View Article : Google Scholar : PubMed/NCBI
69	Fagan DH and Yee D: Crosstalk between IGF1R and estrogen receptor signaling in breast cancer. J Mammary Gland Biol Neoplasia. 13:423–429. 2008. View Article : Google Scholar : PubMed/NCBI
70	Lee AV, Darbre P and King RJ: Processing of insulin-like growth factor-II (IGF-II) by human breast cancer cells. Mol Cell Endocrinol. 99:211–220. 1994. View Article : Google Scholar : PubMed/NCBI
71	Umayahara Y, Kawamori R, Watada H, et al: Estrogen regulation of the insulin-like growth factor I gene transcription involves an AP-1 enhancer. J Biol Chem. 269:16433–16442. 1994.PubMed/NCBI
72	Salerno M, Sisci D, Mauro L, Guvakova MA, Ando S and Surmacz E: Insulin receptor substrate 1 is a target for the pure antiestrogen ICI 182,780 in breast cancer cells. Int J Cancer. 81:299–304. 1999. View Article : Google Scholar : PubMed/NCBI
73	Becker MA, Ibrahim YH, Cui X, Lee AV and Yee D: The IGF pathway regulates ERα through a S6K1-dependent mechanism in breast cancer cells. Mol Endocrinol. 25:516–528. 2011.
74	Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S and Nakshatri H: Phosphatidylinositol 3-kinase/AKT- mediated activation of estrogen receptor α: a new model for anti-estrogen resistance. J Biol Chem. 276:9817–9824. 2001.
75	Ahn BY, Elwi AN, Lee B, et al: Genetic screen identifies insulin-like growth factor binding protein 5 as a modulator of tamoxifen resistance in breast cancer. Cancer Res. 70:3013–3019. 2010. View Article : Google Scholar : PubMed/NCBI
76	Beattie J, Allan GJ, Lochrie JD and Flint DJ: Insulin-like growth factor-binding protein-5 (IGFBP-5): a critical member of the IGF axis. Biochem J. 395:1–19. 2006. View Article : Google Scholar : PubMed/NCBI
77	Akkiprik M, Feng Y, Wang H, et al: Multifunctional roles of insulin-like growth factor binding protein 5 in breast cancer. Breast Cancer Res. 10:2122008. View Article : Google Scholar : PubMed/NCBI
78	Bunone G, Briand PA, Miksicek RJ and Picard D: Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation. EMBO J. 15:2174–2183. 1996.PubMed/NCBI
79	Parisot JP, Hu XF, DeLuise M and Zalcberg JR: Altered expression of the IGF-1 receptor in a tamoxifen-resistant human breast cancer cell line. Br J Cancer. 79:693–700. 1999. View Article : Google Scholar : PubMed/NCBI
80	Knowlden JM, Hutcheson IR, Barrow D, Gee JM and Nicholson RI: Insulin-like growth factor-I receptor signaling in tamoxifen-resistant breast cancer: a supporting role to the epidermal growth factor receptor. Endocrinology. 146:4609–4618. 2005. View Article : Google Scholar : PubMed/NCBI
81	Cohen BD, Baker DA, Soderstrom C, et al: Combination therapy enhances the inhibition of tumor growth with the fully human anti-type 1 insulin-like growth factor receptor monoclonal antibody CP-751,871. Clin Cancer Res. 11:2063–2073. 2005. View Article : Google Scholar : PubMed/NCBI
82	Lu Y, Zi X, Zhao Y, Mascarenhas D and Pollak M: Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). J Natl Cancer Inst. 93:1852–1857. 2001. View Article : Google Scholar : PubMed/NCBI
83	Bouton AH, Riggins RB and Bruce-Staskal PJ: Functions of the adapter protein Cas: signal convergence and the determination of cellular responses. Oncogene. 20:6448–6458. 2001. View Article : Google Scholar : PubMed/NCBI
84	Defilippi P, Di Stefano P and Cabodi S: p130Cas: a versatile scaffold in signaling networks. Trends Cell Biol. 16:257–263. 2006. View Article : Google Scholar : PubMed/NCBI
85	Lu Y, Mani S, Kandimalla ER, et al: The Cockayne syndrome group B DNA repair protein as an anti-cancer target. Int J Oncol. 19:1089–1097. 2001.PubMed/NCBI
86	Planas-Silva MD and Hamilton KN: Targeting c-Src kinase enhances tamoxifen’s inhibitory effect on cell growth by modulating expression of cell cycle and survival proteins. Cancer Chemother Pharmacol. 60:535–543. 2007.PubMed/NCBI
87	Schuh NR, Guerrero MS, Schrecengost RS and Bouton AH: BCAR3 regulates Src/p130 Cas association, Src kinase activity, and breast cancer adhesion signaling. J Biol Chem. 285:2309–2317. 2010. View Article : Google Scholar : PubMed/NCBI
88	Gotoh T, Cai D, Tian X, Feig LA and Lerner A: p130^Cas regulates the activity of AND-34, a novel Ral, Rap1, and R-Ras guanine nucleotide exchange factor. J Biol Chem. 275:30118–30123. 2000.
89	Cai D, Iyer A, Felekkis KN, et al: AND-34/BCAR3, a GDP exchange factor whose overexpression confers antiestrogen resistance, activates Rac, PAK1, and the cyclin D1 promoter. Cancer Res. 63:6802–6808. 2003.PubMed/NCBI
90	van Agthoven T, van Agthoven TL, Dekker A, van der Spek PJ, Vreede L and Dorssers LC: Identification of BCAR3 by a random search for genes involved in antiestrogen resistance of human breast cancer cells. EMBO J. 17:2799–2808. 1998.PubMed/NCBI
91	Felekkis KN, Narsimhan RP, Near R, et al: AND-34 activates phosphatidylinositol 3-kinase and induces anti-estrogen resistance in a SH2 and GDP exchange factor-like domain-dependent manner. Mol Cancer Res. 3:32–41. 2005.PubMed/NCBI
92	Liu P, Cheng H, Roberts TM and Zhao JJ: Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 8:627–644. 2009. View Article : Google Scholar : PubMed/NCBI
93	Miller TW, Balko JM and Arteaga CL: Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J Clin Oncol. 29:4452–4461. 2011. View Article : Google Scholar : PubMed/NCBI
94	Fox EM, Arteaga CL and Miller TW: Abrogating endocrine resistance by targeting ERα and PI3K in breast cancer. Front Oncol. 2:1452012.
95	Turner N, Pearson A, Sharpe R, et al: FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res. 70:2085–2094. 2010. View Article : Google Scholar
96	van der Kaay J, Cullen PJ and Downes CP: Phosphatidylinositol(3,4,5)trisphosphate (Ptdins(3,4,5)P₃) mass measurement using a radioligand displacement assay. Methods Mol Biol. 105:109–125. 1998.
97	Maehama T and Dixon JE: The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 273:13375–13378. 1998. View Article : Google Scholar : PubMed/NCBI
98	Massarweh S and Schiff R: Unraveling the mechanisms of endocrine resistance in breast cancer: new therapeutic opportunities. Clin Cancer Res. 13:1950–1954. 2007. View Article : Google Scholar : PubMed/NCBI
99	Lewis-Wambi JS and Jordan VC: Estrogen regulation of apoptosis: how can one hormone stimulate and inhibit? Breast Cancer Res. 11:2062009. View Article : Google Scholar : PubMed/NCBI
100	Schiff R, Reddy P, Ahotupa M, et al: Oxidative stress and AP-1 activity in tamoxifen-resistant breast tumors in vivo. J Natl Cancer Inst. 92:1926–1934. 2000. View Article : Google Scholar : PubMed/NCBI
101	Nair BC and Vadlamudi RK: Regulation of hormonal therapy resistance by cell cycle machinery. Gene Ther Mol Biol. 12:3952008.PubMed/NCBI
102	Butt AJ, McNeil CM, Musgrove EA and 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. 12(Suppl 10): S47–S59. 2005. View Article : Google Scholar : PubMed/NCBI
103	Kilker RL, Hartl MW, Rutherford TM and Planas-Silva MD: Cyclin D1 expression is dependent on estrogen receptor function in tamoxifen-resistant breast cancer cells. J Steroid Biochem Mol Biol. 92:63–71. 2004. View Article : Google Scholar : PubMed/NCBI
104	Zwijsen RM, Wientjens E, Klompmaker R, van der Sman J, Bernards R and Michalides RJ: CDK-independent activation of estrogen receptor by cyclin D1. Cell. 88:405–415. 1997. View Article : Google Scholar : PubMed/NCBI
105	Wilcken NR, Prall OW, Musgrove EA and Sutherland RL: Inducible overexpression of cyclin D1 in breast cancer cells reverses the growth-inhibitory effects of antiestrogens. Clin Cancer Res. 3:849–854. 1997.PubMed/NCBI
106	Osborne CK and Schiff R: Growth factor receptor cross-talk with estrogen receptor as a mechanism for tamoxifen resistance in breast cancer. Breast. 12:362–367. 2003. View Article : Google Scholar : PubMed/NCBI
107	Rudas M, Lehnert M, Huynh A, et al: Cyclin D1 expression in breast cancer patients receiving adjuvant tamoxifen-based therapy. Clin Cancer Res. 14:1767–1774. 2008. View Article : Google Scholar : PubMed/NCBI
108	Stendahl M, Kronblad A, Rydén L, Emdin S, Bengtsson NO and Landberg G: Cyclin D1 overexpression is a negative predictive factor for tamoxifen response in postmenopausal breast cancer patients. Br J Cancer. 90:1942–1948. 2004. View Article : Google Scholar : PubMed/NCBI
109	Sieuwerts AM, Look MP, Meijer-van Gelder ME, et al: Which cyclin E prevails as prognostic marker for breast cancer? Results from a retrospective study involving 635 lymph node-negative breast cancer patients. Clin Cancer Res. 12:3319–3328. 2006. View Article : Google Scholar : PubMed/NCBI
110	Bosco EE, Wang Y, Xu H, et al: The retinoblastoma tumor suppressor modifies the therapeutic response of breast cancer. J Clin Invest. 117:218–228. 2007. View Article : Google Scholar : PubMed/NCBI
111	Musgrove EA, Sergio CM, Anderson LR, et al: Identification of downstream targets of estrogen and c-myc in breast cancer cells. Adv Exp Med Biol. 617:445–451. 2008. View Article : Google Scholar : PubMed/NCBI
112	Dhillon NK and Mudryj M: Ectopic expression of cyclin E in estrogen responsive cells abrogates antiestrogen mediated growth arrest. Oncogene. 21:4626–4634. 2002. View Article : Google Scholar : PubMed/NCBI
113	Hui R, Finney GL, Carroll JS, Lee CS, Musgrove EA and Sutherland RL: Constitutive overexpression of cyclin D1 but not cyclin E confers acute resistance to antiestrogens in T-47D breast cancer cells. Cancer Res. 62:6916–6923. 2002.PubMed/NCBI
114	Caldon CE, Sergio CM, Schütte J, et al: Estrogen regulation of cyclin E2 requires cyclin D1 but not c-Myc. Mol Cell Biol. 29:4623–4639. 2009. View Article : Google Scholar : PubMed/NCBI
115	Finn RS, Dering J, Conklin D, 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. 11:R772009. View Article : Google Scholar
116	Wang L, Wang J, Blaser BW, et al: Pharmacologic inhibition of CDK4/6: mechanistic evidence for selective activity or acquired resistance in acute myeloid leukemia. Blood. 110:2075–2083. 2007. View Article : Google Scholar : PubMed/NCBI
117	Planas-Silva MD and Weinberg RA: Estrogen-dependent cyclin E-cdk2 activation through p21 redistribution. Mol Cell Biol. 17:4059–4069. 1997.PubMed/NCBI
118	Cariou S, Donovan JC, Flanagan WM, Milic A, Bhattacharya N and Slingerland JM: Down-regulation of p21^WAF1/CIP1 or p27^Kip1 abrogates antiestrogen-mediated cell cycle arrest in human breast cancer cells. Proc Natl Acad Sci USA. 97:9042–9046. 2000.PubMed/NCBI
119	Bachman KE, Blair BG, Brenner K, et al: p21^WAF1/CIP1 mediates the growth response to TGF-β in human epithelial cells. Cancer Biol Ther. 3:221–225. 2004.
120	Mokbel K: The evolving role of aromatase inhibitors in breast cancer. Int J Clin Oncol. 7:279–283. 2002.PubMed/NCBI
121	Jordan VC: Tamoxifen (ICI46,474) as a targeted therapy to treat and prevent breast cancer. Br J Pharmacol. 147(Suppl 1): S269–S276. 2006. View Article : Google Scholar : PubMed/NCBI
122	Pohl G, Rudas M, Dietze O, et al: High p27^Kip1 expression predicts superior relapse-free and overall survival for premenopausal women with early-stage breast cancer receiving adjuvant treatment with tamoxifen plus goserelin. J Clin Oncol. 21:3594–3600. 2003.
123	Abukhdeir AM and Park BH: P21 and p27: roles in carcinogenesis and drug resistance. Expert Rev Mol Med. 10:e192008. View Article : Google Scholar : PubMed/NCBI
124	Ellis PA, Smith IE, Detre S, et al: Reduced apoptosis and proliferation and increased Bcl-2 in residual breast cancer following preoperative chemotherapy. Breast Cancer Res Treat. 48:107–116. 1998. View Article : Google Scholar : PubMed/NCBI
125	Cannings E, Kirkegaard T, Tovey SM, Dunne B, Cooke TG and Bartlett JM: Bad expression predicts outcome in patients treated with tamoxifen. Breast Cancer Res Treat. 102:173–179. 2007. View Article : Google Scholar : PubMed/NCBI
126	Hur J, Chesnes J, Coser KR, et al: The Bik BH3-only protein is induced in estrogen-starved and antiestrogen-exposed breast cancer cells and provokes apoptosis. Proc Natl Acad Sci USA. 101:2351–2356. 2004. View Article : Google Scholar : PubMed/NCBI
127	Fu Y, Li J and Lee AS: GRP78/BiP inhibits endoplasmic reticulum BIK and protects human breast cancer cells against estrogen starvation-induced apoptosis. Cancer Res. 67:3734–3740. 2007. View Article : Google Scholar
128	Viedma-Rodriguez R, Baiza-Gutman LA, García-Carrancá A, Moreno-Fierros L, Salamanca-Gómez F and Arenas-Aranda D: Suppression of the death gene BIK is a critical factor for resistance to tamoxifen in MCF-7 breast cancer cells. Int J Oncol. 43:1777–1786. 2013.PubMed/NCBI
129	Lopez J, Hesling C, Prudent J, et al: Src tyrosine kinase inhibits apoptosis through the Erk1/2-dependent degradation of the death accelerator Bik. Cell Death Differ. 19:1459–1469. 2012. View Article : Google Scholar : PubMed/NCBI
130	Schoenlein PV, Periyasamy-Thandavan S, Samaddar JS, Jackson WH and Barrett JT: Autophagy facilitates the progression of ERα-positive breast cancer cells to antiestrogen resistance. Autophagy. 5:400–403. 2009.
131	Galluzzi L, Vicencio JM, Kepp O, Tasdemir E, Maiuri MC and Kroemer G: To die or not to die: that is the autophagic question. Curr Mol Med. 8:78–91. 2008. View Article : Google Scholar : PubMed/NCBI
132	Cully M, You H, Levine AJ and Mak TW: Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer. 6:184–192. 2006. View Article : Google Scholar : PubMed/NCBI
133	Shaw RJ and Cantley LC: Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature. 441:424–430. 2006. View Article : Google Scholar : PubMed/NCBI
134	Degenhardt K, Mathew R, Beaudoin B, et al: Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell. 10:51–64. 2006. View Article : Google Scholar : PubMed/NCBI
135	Feng W, Huang S, Wu H and Zhang M: Molecular basis of Bcl-xL’s target recognition versatility revealed by the structure of Bcl-xL in complex with the BH3 domain of Beclin-1. J Mol Biol. 372:223–235. 2007.
136	Ciechomska IA, Goemans GC, Skepper JN and Tolkovsky AM: Bcl-2 complexed with Beclin-1 maintains full anti-apoptotic function. Oncogene. 28:2128–2141. 2009. View Article : Google Scholar : PubMed/NCBI
137	Maiuri MC, Le Toumelin G, Criollo A, et al: Functional and physical interaction between Bcl-X_L and a BH3-like domain in Beclin-1. EMBO J. 26:2527–2539. 2007. View Article : Google Scholar : PubMed/NCBI
138	Levine B, Sinha S and Kroemer G: Bcl-2 family members: dual regulators of apoptosis and autophagy. Autophagy. 4:600–606. 2008. View Article : Google Scholar : PubMed/NCBI
139	Boyd JM, Gallo GJ, Elangovan B, et al: Bik, a novel death-inducing protein shares a distinct sequence motif with Bcl-2 family proteins and interacts with viral and cellular survival-promoting proteins. Oncogene. 11:1921–1928. 1995.PubMed/NCBI
140	Naumann U, Bähr O, Wolburg H, et al: Adenoviral expression of XIAP antisense RNA induces apoptosis in glioma cells and suppresses the growth of xenografts in nude mice. Gene Ther. 14:147–161. 2007. View Article : Google Scholar : PubMed/NCBI
141	Oppermann M, Geilen CC, Fecker LF, Gillissen B, Daniel PT and Eberle J: Caspase-independent induction of apoptosis in human melanoma cells by the proapoptotic Bcl-2-related protein Nbk/Bik. Oncogene. 24:7369–7380. 2005. View Article : Google Scholar : PubMed/NCBI
142	Garcia N, Salamanca F, Astudillo-de la Vega H, et al: A molecular analysis by gene expression profiling reveals Bik/NBK overexpression in sporadic breast tumor samples of Mexican females. BMC Cancer. 5:932005. View Article : Google Scholar : PubMed/NCBI
143	Hirsch DS, Shen Y, Dokmanovic M and Wu WJ: pp60^c-Src phosphorylates and activates vacuolar protein sorting 34 to mediate cellular transformation. Cancer Res. 70:5974–5983. 2010.
144	Gao P, Bauvy C, Souquère S, et al: The Bcl-2 homology domain 3 mimetic gossypol induces both Beclin 1-dependent and Beclin 1-independent cytoprotective autophagy in cancer cells. J Biol Chem. 285:25570–25581. 2010. View Article : Google Scholar : PubMed/NCBI
145	Furuya N, Yu J, Byfield M, Pattingre S and Levine B: The evolutionarily conserved domain of Beclin 1 is required for Vps34 binding, autophagy and tumor suppressor function. Autophagy. 1:46–52. 2005. View Article : Google Scholar : PubMed/NCBI
146	Musgrove EA and Sutherland RL: Biological determinants of endocrine resistance in breast cancer. Nat Rev Cancer. 9:631–643. 2009. View Article : Google Scholar : PubMed/NCBI
147	Dancey J: mTOR signaling and drug development in cancer. Nat Rev Clin Oncol. 7:209–219. 2010. View Article : Google Scholar : PubMed/NCBI
148	Ciafrè SA, Galardi S, Mangiola A, et al: Extensive modulation of a set of microRNAs in primary glioblastoma. Biochem Biophys Res Commun. 334:1351–1358. 2005.PubMed/NCBI
149	Pallante P, Visone R, Ferracin M, et al: MicroRNA deregulation in human thyroid papillary carcinomas. Endocr Relat Cancer. 13:497–508. 2006. View Article : Google Scholar : PubMed/NCBI
150	Kondo N, Toyama T, Sugiura H, Fujii Y and Yamashita H: miR-206 expression is down-regulated in estrogen receptor α-positive human breast cancer. Cancer Res. 68:5004–5008. 2008.
151	Rao X, Di Leva G, Li M, et al: MicroRNA-221/222 confers breast cancer fulvestrant resistance by regulating multiple signaling pathways. Oncogene. 30:1082–1097. 2011. View Article : Google Scholar : PubMed/NCBI
152	Sachdeva M, Wu H, Ru P, Hwang L, Trieu V and Mo YY: MicroRNA-101-mediated Akt activation and estrogen-independent growth. Oncogene. 30:822–831. 2011. View Article : Google Scholar : PubMed/NCBI
153	Miller TE, Ghoshal K, Ramaswamy B, et al: MicroRNA-221/222 confers tamoxifen resistance in breast cancer by targeting p27^Kip1. J Biol Chem. 283:29897–29903. 2008. View Article : Google Scholar : PubMed/NCBI
154	Kovalchuk O, Filkowski J, Meservy J, et al: Involvement of microRNA-451 in resistance of the MCF-7 breast cancer cells to chemotherapeutic drug doxorubicin. Mol Cancer Ther. 7:2152–2159. 2008. View Article : Google Scholar : PubMed/NCBI
155	Liang Z, Wu H, Xia J, et al: Involvement of miR-326 in chemotherapy resistance of breast cancer through modulating expression of multidrug resistance-associated protein 1. Biochem Pharmacol. 79:817–824. 2010. View Article : Google Scholar
156	Xin F, Li M, Balch C, et al: Computational analysis of microRNA profiles and their target genes suggests significant involvement in breast cancer antiestrogen resistance. Bioinformatics. 25:430–434. 2009. View Article : Google Scholar
157	Guardavaccaro D and Clevers H: Wnt/β-catenin and MAPK signaling: allies and enemies in different battlefields. Sci Signal. 5:pe152012.
158	Gabrovska PN, Smith RA, Tiang T, Weinstein SR, Haupt LM and Griffiths LR: Development of an eight gene expression profile implicating human breast tumours of all grade. Mol Biol Rep. 39:3879–3892. 2012. View Article : Google Scholar
159	Khramtsov AI, Khramtsova GF, Tretiakova M, Huo D, Olopade OI and Goss KH: Wnt/β-catenin pathway activation is enriched in basal-like breast cancers and predicts poor outcome. Am J Pathol. 176:2911–2920. 2010.
160	Loh YN, Hedditch EL, Baker LA, Jary E, Ward RL and Ford CE: The Wnt signalling pathway is upregulated in an in vitro model of acquired tamoxifen resistant breast cancer. BMC Cancer. 13:1742013. View Article : Google Scholar : PubMed/NCBI
161	Katoh M: Comparative genomics on Wnt3-Wnt9b gene cluster. Int J Mol Med. 15:743–747. 2005.PubMed/NCBI
162	Rubin JS, Bottaro DP, Chedid M, et al: Keratinocyte growth factor. Cell Biol Int. 19:399–411. 1995. View Article : Google Scholar
163	Rubin JS, Bottaro DP, Chedid M, et al: Keratinocyte growth factor as a cytokine that mediates mesenchymal-epithelial interaction. EXS. 74:191–214. 1995.PubMed/NCBI
164	Kumar V, Green S, Staub A and Chambon P: Localisation of the oestradiol-binding and putative DNA-binding domains of the human oestrogen receptor. EMBO J. 5:2231–2236. 1986.PubMed/NCBI
165	Berry M, Metzger D and Chambon P: Role of the two activating domains of the oestrogen receptor in the cell-type and promoter-context dependent agonistic activity of the anti-oestrogen 4-hydroxytamoxifen. EMBO J. 9:2811–2818. 1990.
166	Mader S, Chambon P and White JH: Defining a minimal estrogen receptor DNA binding domain. Nucleic Acids Res. 21:1125–1132. 1993. View Article : Google Scholar : PubMed/NCBI
167	Wang Z, Li Y, Banerjee S and Sarkar FH: Emerging role of Notch in stem cells and cancer. Cancer Lett. 279:8–12. 2009. View Article : Google Scholar : PubMed/NCBI
168	Shi TP, Xu H, Wei JF, et al: Association of low expression of notch-1 and jagged-1 in human papillary bladder cancer and shorter survival. J Urol. 180:361–366. 2008. View Article : Google Scholar : PubMed/NCBI
169	Al Saleh S, Sharaf LH and Luqmani YA: Signalling pathways involved in endocrine resistance in breast cancer and associations with epithelial to mesenchymal transition (Review). Int J Oncol. 38:1197–1217. 2011.PubMed/NCBI
170	Dontu G, Jackson KW, McNicholas E, Kawamura MJ, Abdallah WM and Wicha MS: Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Res. 6:R605–R615. 2004. View Article : Google Scholar : PubMed/NCBI
171	Stylianou S, Clarke RB and Brennan K: Aberrant activation of notch signaling in human breast cancer. Cancer Res. 66:1517–1525. 2006. View Article : Google Scholar : PubMed/NCBI
172	Rizzo P, Miao H, D’Souza G, et al: Cross-talk between notch and the estrogen receptor in breast cancer suggests novel therapeutic approaches. Cancer Res. 68:5226–5235. 2008. View Article : Google Scholar : PubMed/NCBI
173	Wang Z, Li Y, Ahmad A, et al: Targeting Notch signaling pathway to overcome drug resistance for cancer therapy. Biochim Biophys Acta. 1806:258–267. 2010.PubMed/NCBI
174	Hurvitz SA and Pietras RJ: Rational management of endocrine resistance in breast cancer: a comprehensive review of estrogen receptor biology, treatment options, and future directions. Cancer. 113:2385–2397. 2008. View Article : Google Scholar
175	Dibb NJ, Dilworth SM and Mol CD: Switching on kinases: oncogenic activation of BRAF and the PDGFR family. Nat Rev Cancer. 4:718–727. 2004. View Article : Google Scholar : PubMed/NCBI
176	Weigel MT, Ghazoui Z, Dunbier A, Pancholi S, Dowsett M and Martin LA: Preclinical and clinical studies of estrogen deprivation support the PDGF/Abl pathway as a novel therapeutic target for overcoming endocrine resistance in breast cancer. Breast Cancer Res. 14:R782012. View Article : Google Scholar
177	Pancholi V: Multifunctional α-enolase: its role in diseases. Cell Mol Life Sci. 58:902–920. 2001.
178	Jiang BH, Agani F, Passaniti A and Semenza GL: V-SRC induces expression of hypoxia-inducible factor 1 (HIF-1) and transcription of genes encoding vascular endothelial growth factor and enolase 1: involvement of HIF-1 in tumor progression. Cancer Res. 57:5328–5335. 1997.
179	Wygrecka M, Marsh LM, Morty RE, et al: Enolase-1 promotes plasminogen-mediated recruitment of monocytes to the acutely inflamed lung. Blood. 113:5588–5598. 2009. View Article : Google Scholar : PubMed/NCBI
180	Dudani AK, Cummings C, Hashemi S and Ganz PR: Isolation of a novel 45 kDa plasminogen receptor from human endothelial cells. Thromb Res. 69:185–196. 1993. View Article : Google Scholar : PubMed/NCBI
181	Peebles KA, Duncan MW, Ruch RJ and Malkinson AM: Proteomic analysis of a neoplastic mouse lung epithelial cell line whose tumorigenicity has been abrogated by transfection with the gap junction structural gene for connexin 43, Gja1. Carcinogenesis. 24:651–657. 2003. View Article : Google Scholar
182	Wu W, Tang X, Hu W, Lotan R, Hong WK and Mao L: Identification and validation of metastasis-associated proteins in head and neck cancer cell lines by two-dimensional electrophoresis and mass spectrometry. Clin Exp Metastasis. 19:319–326. 2002. View Article : Google Scholar : PubMed/NCBI
183	Ray R and Miller DM: Cloning and characterization of a human c-myc promoter-binding protein. Mol Cell Biol. 11:2154–2161. 1991.PubMed/NCBI
184	Tu SH, Chang CC, Chen CS, et al: Increased expression of enolase α in human breast cancer confers tamoxifen resistance in human breast cancer cells. Breast Cancer Res Treat. 121:539–553. 2010.