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ER reprogramming promotes a select pro-metastatic secretome in high FOXA1-expressing ER-positive endocrine-resistant and metastatic breast cancer

ABSTRACT: ER reprogramming promotes a select pro-metastatic secretome in high FOXA1-expressing ER-positive endocrine-resistant and metastatic breast cancer

PROVIDER: PRJNA732366 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14631620.fastq.gz	Fastqsanger.gz
	SRR14631621.fastq.gz	Fastqsanger.gz
	SRR14631622.fastq.gz	Fastqsanger.gz
	SRR14631623.fastq.gz	Fastqsanger.gz
	SRR14631624.fastq.gz	Fastqsanger.gz

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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.

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ER reprogramming promotes a select pro-metastatic secretome in high FOXA1-expressing ER-positive endocrine-resistant and metastatic breast cancer

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