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Chromatin profile-based identification of a novel ER-positive breast cancer subgroup with reduced ER-responsive element accessibility

ABSTRACT: Estrogen receptor (ER) signaling–dependent cancer cell growth is one of the major features of ER-positive breast cancer (BC). Inhibition of ER function is a standard and effective treatment for ER-positive tumors; however, ~20% of patients with ER-positive BC experience early or late recurrence. In this study, we examined intertumor heterogeneity from an epigenetic perspective based on the hypothesis that the intrinsic difference in epigenetic states around ER signaling pathway underlies endocrine therapy resistance. We profiled chromatin accessibility data from 42 BC samples, including 35 ER-positive human epidermal growth factor receptor 2 (HER2)-negative and 7 triple-negative tumors, identifying a subgroup of ER-positive BCs with a distinctive chromatin accessibility pattern including reduced accessibility to ER-responsive elements (EREs). The same subgroup was also observed in The Cancer Genome Atlas BC cohort. Despite the reduced accessibility to EREs, the expression of ER and potential ER target genes were not decreased in these tumors. Our findings highlight the existence of a subset of ER-positive BCs with unchanged ER expression but reduced EREs accessibility that cannot be distinguished by conventional immunostaining for ER. Future studies should determine whether these tumors are associated with resistance to endocrine therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE222116 | GEO | 2023/01/09

REPOSITORIES: GEO

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Project description:Aberrant activation of the forkhead protein FOXA1 is observed in advanced hormone-related cancers. However, to date, key mediators of high FOXA1 signaling remain elusive. We demonstrate that ectopic high FOXA1 (H-FOXA1) expression promotes estrogen receptor-positive (ER+) breast cancer (BC) metastasis in a xenograft mouse model. Mechanistically, H-FOXA1 reprograms ER-chromatin binding to elicit a core gene signature (CGS) highly enriched in ER+ endocrine-resistant (EndoR) cells. We identified Secretome14, a CGS subset encoding ER-dependent cancer secretory proteins, strongly predicts poor outcomes of ER+ BC and is elevated in ER+ metastases vs. primary tumors, irrespective to the ESR1 mutations. Parental (P) ER+ BC cells and their endocrine-resistant (EndoR) derivatives, and ER+ BC cells expressing doxycycline (Dox)-inducible ectopic FOXA1 were used in this study. Differential gene expression analysis was performed in EndoR vs. P cells and P cells +Dox vs. -Dox. We found that the FOXA1-CGS was highly enriched in the altered transcriptomes of two ER+ BC cell models (ZR75-1 and T47D) expressing ectopic H-FOXA1. The enriched hallmark gene sets, shared by the H-FOXA1 cell models, include “inflammatory response”, “complement”, and “interferon gamma response” for the H-FOXA1-induced, and “estrogen response early” and “estrogen response late” for the H-FOXA1-repressed genes. These findings point to the common transcriptional profile exhibiting an immune- over estrogen-responsive signature induced by H-FOXA1. In addition, we found that both the tamoxifen-resistant (TamR) and estrogen deprivation-resistant (EDR) derivatives of the 600MPE P cells were enriched for the H-FOXA1-induced CGS and FOXA1/ER-activated Secretome14. Our findings uncover H-FOXA1-induced ER reprogramming driving EndoR and metastasis, possibly via a H-FOXA1/ER-dependent secretome that warrants further studies to clarify its involvement in disease progression of ER+ metastatic BC.

Project description:Breast cancer is a heterogeneous disease classified into 3 major subtypes based on the presence or absence of molecular markers for oestrogen receptors (ER), progesterone receptors (PR) and human epidermal growth factor-2 (Her2) . Hormone receptor-positive BC (ER+, PR+ and Her-2-), accounts for approximately 70% of patients. Patients with ER- BC account for approximately 30 % of all cases and commonly have a worse prognosis than ER+ patients (9). However, a significant proportion of ER- cases have good outcomes and could potentially benefit from a less aggressive therapy. Triple negative breast cancer (TNBC, ER-, PR- and Her-2-) accounts for approximately 15% of breast cancers and has the poorest outcomes. An hypoxic microenvironment is an important intrinsic component of solid tumours that can result in rapid proliferation of cancer cells and is associated with the lack of oxgyen and abnormal tumour blood vessels. Hypoxia stimulates the hypoxia inducible factor-1α (HIF-1α) that transactivates genes associated with angiogenesis, tumour growth, metastasis, metabolic reprogramming, and treatment resistance. HIF-1α is recognised to induce the expression of carbonic anhydrase IX (CAIX), an enzyme that has been attributed a central role in pH regulation and cancer progression and is particularly pronounced in peri necrotic tumour areas, high-grade BCs. The adaption to hypoxia is governed by multiple transcriptional and post-transcriptional changes in gene expression. Up to 1.5 % of the human genome is estimated to be transcriptionally responsive to hypoxia. Genes and pathways which have been identified as being responsive to hypoxia may have the potential to be used as prognostic or predictive markers, and furthermore, can help identify novel therapeutic targets. The aim of the present study was to gain a better understanding of the transcriptomic and protein pathways associated with CAIX in ER- BC to identify potential therapeutic targets against this aggressive phenotype.

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Chromatin profile-based identification of a novel ER-positive breast cancer subgroup with reduced ER-responsive element accessibility

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