Endocrine therapy is a key treatment strategy to control or eradicate hormone-responsive breast cancer. The most commonly used endocrine therapy agents are selective estrogen receptor modulators (SERMs, e.g. tamoxifen), estrogen synthesis inhibitors (e.g. aromatase inhibitors (AIs) such as anastrozole, letrozole, and exemestane), and selective estrogen receptor down-regulators (SERDs, e.g. fulvestrant). However, resistance to these agents has become a major clinical obstacle. Mechanisms of endocrine resistance include loss of ER-alpha expression, altered expression of coactivators or coregulators that play a critical role in ER-mediated gene transcription, ligand-independent growth factor signaling cascades that activate kinases and ER-phosphorylation, altered availability of active tamoxifen metabolites regulated by drug-metabolizing enzymes, such as CYP2D6, and deregulation of the cell cycle and apoptotic machinery.

Human Diseases; Drug resistance: antineoplastic
BRITE hierarchy

Loxodonta africana (African savanna elephant) [GN:lav]

PMID:23344024

Garcia-Becerra R, Santos N, Diaz 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 14:108-45 (2012)
DOI:10.3390/ijms14010108

PMID:19701242

Musgrove EA, Sutherland RL

Biological determinants of endocrine resistance in breast cancer.

Nat Rev Cancer 9:631-43 (2009)
DOI:10.1038/nrc2713

PMID:22015292

Giuliano M, Schifp R, Osborne CK, Trivedi MV

Biological mechanisms and clinical implications of endocrine resistance in breast cancer.

Breast 20 Suppl 3:S42-9 (2011)
DOI:10.1016/S0960-9776(11)70293-4

PMID:25907219

Ma CX, Reinert T, Chmielewska I, Ellis MJ

Mechanisms of aromatase inhibitor resistance.

Nat Rev Cancer 15:261-75 (2015)
DOI:10.1038/nrc3920

PMID:24841429

Viedma-Rodriguez R, Baiza-Gutman L, Salamanca-Gomez F, Diaz-Zaragoza M, Martinez-Hernandez G, Ruiz Esparza-Garrido R, Velazquez-Flores MA, Arenas-Aranda D

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

Oncol Rep 32:3-15 (2014)
DOI:10.3892/or.2014.3190

PMID:26849149

Luqmani YA, Alam-Eldin N

Overcoming Resistance to Endocrine Therapy in Breast Cancer: New Approaches to a Nagging Problem.

Med Princ Pract 25 Suppl 2:28-40 (2016)
DOI:10.1159/000444451

PMID:22771991

Bianco S, Gevry N

Endocrine resistance in breast cancer: from cellular signaling pathways to epigenetic mechanisms.

Transcription 3:165-70 (2012)
DOI:10.4161/trns.20496

PMID:20887199

Osborne CK, Schiff R

Mechanisms of endocrine resistance in breast cancer.

Annu Rev Med 62:233-47 (2011)
DOI:10.1146/annurev-med-070909-182917

PMID:23714450

Miller TW

Endocrine resistance: what do we know?

Am Soc Clin Oncol Educ Book 0011300037 (2013)
DOI:10.1200/EdBook_AM.2013.33.e37

PMID:23625614

Lonning PE, Eikesdal HP

Aromatase inhibition 2013: clinical state of the art and questions that remain to be solved.

Endocr Relat Cancer 20:R183-201 (2013)
DOI:10.1530/ERC-13-0099

PMID:26473850

Egeland NG, Lunde S, Jonsdottir K, Lende TH, Cronin-Fenton D, Gilje B, Janssen EA, Soiland H

The Role of MicroRNAs as Predictors of Response to Tamoxifen Treatment in Breast Cancer Patients.

Int J Mol Sci 16:24243-75 (2015)
DOI:10.3390/ijms161024243

PMID:24130921

Chang M

Tamoxifen resistance in breast cancer.

Biomol Ther (Seoul) 20:256-67 (2012)
DOI:10.4062/biomolther.2012.20.3.256

PMID:18804516

Zilli M, Grassadonia A, Tinari N, Di Giacobbe A, Gildetti S, Giampietro J, Natoli C, Iacobelli S

Molecular mechanisms of endocrine resistance and their implication in the therapy of breast cancer.

Biochim Biophys Acta 1795:62-81 (2009)
DOI:10.1016/j.bbcan.2008.08.003

PMID:24289103

Mo Z, Liu M, Yang F, Luo H, Li Z, Tu G, Yang G

GPR30 as an initiator of tamoxifen resistance in hormone-dependent breast cancer.

Breast Cancer Res 15:R114 (2013)
DOI:10.1186/bcr3581

PMID:24415977

Hasson SP, Rubinek T, Ryvo L, Wolf I

Endocrine resistance in breast cancer: focus on the phosphatidylinositol 3-kinase/akt/mammalian target of rapamycin signaling pathway.

Breast Care (Basel) 8:248-55 (2013)
DOI:10.1159/000354757

PMID:15613444

Ring A, Dowsett M

Mechanisms of tamoxifen resistance.

Endocr Relat Cancer 11:643-58 (2004)
DOI:10.1677/erc.1.00776

PMID:24565562

Ribeiro JR, Freiman RN

Estrogen signaling crosstalk: Implications for endocrine resistance in ovarian cancer.

J Steroid Biochem Mol Biol 143:160-73 (2014)
DOI:10.1016/j.jsbmb.2014.02.010

PMID:20960099

Wang D, Hu L, Zhang G, Zhang L, Chen C

G protein-coupled receptor 30 in tumor development.

Endocrine 38:29-37 (2010)
DOI:10.1007/s12020-010-9363-z

PMID:26122181

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 12:573-83 (2015)
DOI:10.1038/nrclinonc.2015.117