Growth factor stimulation induces a distinct ERα cistrome underlying breast cancer endocrine resistance

Abstract

Estrogen receptor a (ERa) expression in breast cancer is predictive of response to endocrine therapy; however, resistance is common in ERa-positive tumors that overexpress the growth factor receptor ERBB2. Even in the absence of estrogen, ERa can be activated by growth factors, including the epidermal growth factor (EGF). EGF induces a transcriptional program distinct from estrogen; however, the mechanism of the stimulus-specific response is unknown. Here we show that the EGF-induced ERa genomic targets, its cistromes, are distinct from those induced by estrogen in a process dependent on the transcription factor AP-1. The EGF-induced ERa cistrome specifically regulates genes found overexpressed in ERBB2-positive human breast cancers. This provides a potential molecular explanation for the endocrine therapy resistance seen in ERa-positive breast cancers that overexpress ERBB2. These results suggest a central role for ERa in hormone-refractory breast tumors dependent on growth factor pathway activation and favors the development of therapeutic strategies completely antagonizing ERa, as opposed to blocking its estrogen responsiveness alone.[Keywords: ERBB2; breast cancer; cistrome; estrogen receptor; growth factors; transcription] Supplemental material is available at http://www.genesdev.org.

Nuclear receptors and chromatin: an inducible couple

“…Importantly, oestrogen and EGF can induce ERa recruitment at three classes of enhancers: enhancers bound with stimulation with either oestrogen or EGF, enhancers bound exclusively following oestrogen treatment and enhancers bound exclusively following EGF treatment. These data are in agreement with ligand-specific NR binding (Lupien et al 2010). However, the first class of regulatory elements (e.g.…”

“…ERa can also be activated via growth factor-mediated phosphorylation induced by, for example, tyrosine kinase receptors such as the epidermal growth factor receptor (Kato et al 1995). Genes regulated by phosphorylated ERa are distinct from oestrogen-responsive genes (Lupien et al 2010). Importantly, oestrogen and EGF can induce ERa recruitment at three classes of enhancers: enhancers bound with stimulation with either oestrogen or EGF, enhancers bound exclusively following oestrogen treatment and enhancers bound exclusively following EGF treatment.…”

“…This apparent contradiction is resolved taking into account ERa-mediated post-induction epigenetic modifications. Indeed, a fraction of these shared sites acquire stimulus-specific histone acetylation (H3K18ac; Lupien et al 2010) and correlate with EGF-or oestrogenregulated genes. A recent study probing different classes of ERa ligands has demonstrated that very minute changes in the chemical structure have significant effects on ERa-regulated cellular processes such as proliferation (Srinivasan et al 2013).…”

Emerging functional roles of nuclear receptors in breast cancer

“…This dynamic change in ESR1 action was shown to be influenced by the action of other NRs, such as PGR (Mohammed et al 2015), as well as the signaling context leading to ESR1 activation. For example, ESR1 displayed distinct genomic binding profiles depending on whether ESR1 was activated by estrogen or through the epidermal growth factor (EGF) pathway (Lupien et al 2010). The EGF-induced ESR1 cistrome specifically regulates genes that are overexpressed in ERBB2-positive breast cancers and associated with poor clinical outcomes.…”

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

“…Lupien et al have shown that EGF treatment induces a transcriptional program distinct from estrogen treatment. 45 This different ERα cistrome specifically regulates genes found overexpressed in HER2-positive human breast cancers, explaining endocrine therapy resistance observed in ERα-positive breast cancers that overexpress HER2. in estrogen-responsive breast cancer cells and AE-resistant derivatives have shown significant changes in downstream ERα target gene networks contributing to the acquisition of resistance.…”