Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

• Published in: Oncogene Vol. 29; no. 45; pp. 6071 - 6083
• Main Authors: Aguilar, H, Solé, X, Bonifaci, N, Serra-Musach, J, Islam, A, López-Bigas, N, Méndez-Pertuz, M, Beijersbergen, R L, Lázaro, C, Urruticoechea, A, Pujana, M A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11-11-2010; Nature Publishing Group
• Subjects: 17β-Estradiol; 631/67/1059/2326; 692/699/67/1347; 692/700/565/1331/238; AKT protein; Apoptosis; Aromatase; Aromatase Inhibitors - therapeutic use; Biological and medical sciences; Biological response modifiers; Breast cancer; Breast Neoplasms - drug therapy; Cancer; Care and treatment; Cell Biology; Cell growth; Cell Line, Tumor; Cell physiology; Cell Proliferation; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Drug Resistance, Neoplasm; Drug therapy; Endocrine therapy; ErbB protein; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Estrogen receptors; Estrogens; Female; Fibroblast growth factor receptors; Fundamental and applied biological sciences. Psychology; Gene expression; Genomics; Gynecology. Andrology. Obstetrics; Health aspects; Human Genetics; Humans; Interferon; Internal Medicine; Mammary gland diseases; Medical sciences; Medicine; Medicine & Public Health; Molecular and cellular biology; Molecular modelling; oncogenomics; Oncology; Patient outcomes; Post-menopause; Signal Transduction; Tamoxifen; Tamoxifen - therapeutic use; Transcription factors; Transcriptomes; Transcriptomics; Tumors; Spain; aromatase inhibition; breast cancer; MCF7; estrogen receptor; fibroblast growth factor receptor; long-term estrogen-deprived; Fibroblast growth factor; Estrogen receptor; Breast disease; Enzyme; Estrogen; Breast cancer; Malignant tumor; Estrogen synthase; Carcinogenesis; Ovarian hormone; Resistance; Cellular reprogramming; Mammary gland diseases; Growth factor receptor; Inhibition; Sex steroid hormone; Cancer
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2010.333

Endocrine therapies targeting the proliferative effect of 17β-estradiol through estrogen receptor α (ERα) are the most effective systemic treatment of ERα-positive breast cancer. However, most breast tumors initially responsive to these therapies develop resistance through molecular mechanisms that are not yet fully understood. The long-term estrogen-deprived (LTED) MCF7 cell model has been proposed to recapitulate acquired resistance to aromatase inhibitors in postmenopausal women. To elucidate this resistance, genomic, transcriptomic and molecular data were integrated into the time course of MCF7–LTED adaptation. Dynamic and widespread genomic changes were observed, including amplification of the
ESR1
locus consequently linked to an increase in ERα. Dynamic transcriptomic profiles were also observed that correlated significantly with genomic changes and were predicted to be influenced by transcription factors known to be involved in acquired resistance or cell proliferation (for example, interferon regulatory transcription factor 1 and E2F1, respectively) but, notably, not by canonical ERα transcriptional function. Consistently, at the molecular level, activation of growth factor signaling pathways by EGFR/ERBB/AKT and a switch from phospho-Ser118 (pS118)- to pS167-ERα were observed during MCF7–LTED adaptation. Evaluation of relevant clinical settings identified significant associations between MCF7–LTED and breast tumor transcriptome profiles that characterize ERα-negative status, early response to letrozole and tamoxifen, and recurrence after tamoxifen treatment. In accordance with these profiles, MCF7–LTED cells showed increased sensitivity to inhibition of FGFR-mediated signaling with PD173074. This study provides mechanistic insight into acquired resistance to endocrine therapies of breast cancer and highlights a potential therapeutic strategy.