Dataset Information

Delineation of a FOXA1/ER?/AGR2 regulatory loop that is dysregulated in endocrine therapy-resistant breast cancer.

ABSTRACT: UNLABELLED:Tamoxifen, a selective estrogen receptor (ER) modulator (SERM), remains a frontline clinical therapy for patients with ER?-positive breast cancer. However, the relatively rapid development of resistance to this drug in the metastatic setting remains an impediment to a durable response. Although drug resistance likely arises by many different mechanisms, the consensus is that most of the implicated pathways facilitate the outgrowth of a subpopulation of cancer cells that can either recognize tamoxifen as an agonist or bypass the regulatory control of ER?. Notable in this regard is the observation here and in other studies that expression of anterior gradient homology 2 (AGR2), a known proto-oncogene and disulfide isomerase, was induced by both estrogen (17?-estradiol, E2) and 4-hydroxytamoxifen (4OHT) in breast cancer cells. The importance of AGR2 expression is highlighted here by the observation that (i) its knockdown inhibited the growth of both tamoxifen-sensitive and -resistant breast cancer cells and (ii) its increased expression enhanced the growth of ER?-positive tumors in vivo and increased the migratory capacity of breast cancer cells in vitro. Interestingly, as with most ER? target genes, the expression of AGR2 in all breast cancer cells examined requires the transcription factor FOXA1. However, in tamoxifen-resistant cells, the expression of AGR2 occurs in a constitutive manner, requiring FOXA1, but loses its dependence on ER. Taken together, these data define the importance of AGR2 in breast cancer cell growth and highlight a mechanism where changes in FOXA1 activity obviate the need for ER in the regulation of this gene. IMPLICATIONS:These findings reveal the transcriptional interplay between FOXA1 and ER? in controlling AGR2 during the transition from therapy-sensitive to -resistant breast cancer and implicate AGR2 as a relevant therapeutic target.

SUBMITTER: Wright TM

PROVIDER: S-EPMC4272635 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Delineation of a FOXA1/ERα/AGR2 regulatory loop that is dysregulated in endocrine therapy-resistant breast cancer.

Wright Tricia M TM Wardell Suzanne E SE Jasper Jeff S JS Stice James P JP Safi Rachid R Nelson Erik R ER McDonnell Donald P DP

Molecular cancer research : MCR 20140806 12

<h4>Unlabelled</h4>Tamoxifen, a selective estrogen receptor (ER) modulator (SERM), remains a frontline clinical therapy for patients with ERα-positive breast cancer. However, the relatively rapid development of resistance to this drug in the metastatic setting remains an impediment to a durable response. Although drug resistance likely arises by many different mechanisms, the consensus is that most of the implicated pathways facilitate the outgrowth of a subpopulation of cancer cells that can ei ...[more]

PMID: 25100862

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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.

Dataset Information

Delineation of a FOXA1/ER?/AGR2 regulatory loop that is dysregulated in endocrine therapy-resistant breast cancer.

Publications

Delineation of a FOXA1/ERα/AGR2 regulatory loop that is dysregulated in endocrine therapy-resistant breast cancer.

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