Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

Abstract

Endocrine therapies targeting the proliferative effect of 17b-estradiol through estrogen receptor a (ERa) are the most effective systemic treatment of ERa-positive breast cancer. However, most breast tumors initially responsive to these therapies develop resistance through molecular mechanisms that are not yet fully understood. The longterm 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 ERa. 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 ERa 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-ERa were observed during MCF7-LTED adaptation. Evaluation of relevant clinical settings identified significant associations between MCF7-LTED and breast tumor transcriptome profiles that characterize ERa-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.

Genome-wide activity of unliganded estrogen receptor-α in breast cancer cells

“…Ligand-independent activity of ERα was reported by several groups on individual genes (3)(4)(5). Genomewide ERα binding in the absence of estrogen was also described in breast cancer cells acquainted with growing in hormonedepleted media (6)(7)(8) and in mouse uterus (9). These data suggest that ERα may have a wide genomic function in breast cancer cells independent of its ligands.…”

Genome-wide reprogramming of the chromatin landscape underlies endocrine therapy resistance in breast cancer

“…The transcriptional programs differ significantly between ET-resistant and -responsive breast cancer cells (27)(28)(29), including ET-responsive MCF7 and ET-resistant MCF7-long-term estrogen-deprived (LTED) cells, which gradually acquire resistance upon culture in estrogen/steroid-free conditions modeling aromatase inhibitor resistance (26,(30)(31)(32). Indeed, expression profiling identified 3,230 genes preferentially expressed in LTED and 3,794 genes preferentially expressed in parental MCF7 cells (cutoff at P < 5 × e −2 ) ( Fig.…”

Estrogen receptor alpha gene amplification in breast cancer: 25 years of debate

“…Indeed, this mechanism has been suggested in two independent studies that observed focal ESR1 amplifications of lowlevel copy number change in long-term estrogendeprived (LTED) MCF7 breast cancer cell lines, with use of DNA-specific gene chips and qPCR for ESR1 copy number determination. And yet another experimental study showed that breast-cancer-derived xenografts respond to estrogen treatment of tumor cells that harbor ESR1 amplification, as determined by NGS [89,101] . Furthermore, in one clinical phase Ⅱ study for evaluating anti-estrogen treatment, a focal ESR1 amplification appeared after therapy in one out of 49 tumors analyzed by NGS [102] .…”

“…There is growing evidence that low-level gene copy number amplifications represent an adaptation by tissues to selective pressures [89,101] , even in normal (non-transformed) cells [62] . It is obvious that such alterations in growthregulating pathways can increase the risk for cancerous outgrowth [10,93] .…”