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Conserved Role of FOXC1 in TNBC is parallel to FOXA1 in ER+ Breast Cancer

ABSTRACT: Triple-negative breast cancer (TNBC) is characterized by lack of receptors, estrogen (ER), progesterone, and Her2, and standard receptor-targeted therapies are ineffective. FOXC1, a transcriptional factor aberrantly overexpressed in many cancers, drives growth, metastasis, and stem-cell-like properties in TNBC. However, the molecular function of FOXC1 is unknown, partly due to heterogeneity of TNBC. Here, we show that although FOXC1 regulates many cancer hallmarks in TNBC, its function is varied in different cell lines, highlighted by the differential response to CDK4/6 inhibitors upon FOXC1 loss. Despite this functional heterogeneity, we show that FOXC1 regulates key oncogenes and tumor suppressors and identify a set of core FOXC1 peaks conserved across TNBC cell lines. We identify the ER-associated and drug-targetable nuclear receptor NR2F2 as a cofactor of FOXC1. Finally, we show that core FOXC1 targets in TNBC are parallelly regulated by the pioneer factor FOXA1 and the nuclear receptor NR2F2 in ER+ breast cancer.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Evangelia Papachristou

LAB HEAD: Fahad R. Ali

PROVIDER: PXD053261 | Pride | 2024-07-03

REPOSITORIES: Pride

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			Action	DRS
	QE_HF_07012022_PR1498_EVP_FOXC1_Bt549_R1.msf	Msf
	QE_HF_07012022_PR1498_EVP_FOXC1_Bt549_R1.raw	Raw
	QE_HF_07012022_PR1498_EVP_FOXC1_Bt549_R2.msf	Msf
	QE_HF_07012022_PR1498_EVP_FOXC1_Bt549_R2.raw	Raw
	QE_HF_07012022_PR1498_EVP_FOXC1_Hs578t_R1.msf	Msf

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Project description:Breast cancer is a heterogeneous disease for which prognosis and treatment strategies are largely governed by the receptor status (estrogen, progesterone and Her2-neu) of the tumor cells. Gene expression profiling of whole breast tumors further stratifies breast cancer into several molecular subtypes which also co-segregate with the receptor status of the tumor cells. We postulated that cancer associated fibroblasts (CAFs) within the tumor stroma may exhibit subtype specific gene expression profiles and thus contribute to the biology of the disease in a subtype specific manner. Several studies have reported gene expression profile differences between CAFs and normal breast fibroblasts but in none of these studies were the results stratified based on tumor subtypes. To address whether gene expression in breast cancer associated fibroblasts varies between breast cancer subtypes, we compared the gene expression profiles of early passage primary CAFs isolated from twenty human breast cancer samples representing three main subtypes; seven ER+, seven triple negative (TNBC) and six Her2+. We observed significant expression differences between CAFs derived from Her2+ breast cancer and CAFs from TNBC and ER+ cancers, particularly in pathways associated with cytoskeleton and integrin signaling. In the case of Her2+ breast cancer, the signaling pathways found to be selectively up regulated in CAFs may contribute to the more invasive properties and unfavorable prognosis of Her2+ breast cancer. These data demonstrate that in addition to the distinct molecular profiles that characterize the neoplastic cells, CAF gene expression is also differentially regulated in distinct subtypes of breast cancer. We isolated CAFs from twenty primary breast cancer samples representing three main subtypes (ER+ (n=7), TNBC (n=7), Her2+ (n=6)) and performed gene expression profile analyses on RNA isolated from these early passage CAFs. Those samples were done in two batches with 4 samples repeated in both batches. One TNBC sample was found to be an outlier and not used in the analysis.

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Conserved Role of FOXC1 in TNBC is parallel to FOXA1 in ER+ Breast Cancer

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