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Characterization and therapeutic repercussion of the ecology in HER2 positive breast cancer

ABSTRACT: Conditioned medium experiments carried out in our laboratory with CAFs derived from HER2-positive patients showed a significant capacity to promote resistance to trastuzumab plus pertuzumab therapies in two HER2-positive breast cancer cell lines (BCCLs), even in the presence of docetaxel. In order to elucidate the components of CAF-conditioned medium that would be relevant in the promotion of BCCL resistance, we performed a multi-omics strategy to identify miRNAs, cytokines, transcription factors and/or kinases in the secretome that target specific objectives in cancer cells. The combination of miRNA analysis, label-free LC-MS/MS quantification and cytokine arrays to explore the secretome of CAFs under treatment conditions revealed several up- and down-regulated candidates. We discuss the potential role of some of the most interesting candidates in generating resistance in HER2-positive breast cancer

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Breast, Fibroblast Of Mammary Gland

DISEASE(S): Breast Cancer

SUBMITTER: Concha Gil

LAB HEAD: Juan Madoz-Gúrpide

PROVIDER: PXD025556 | Pride | 2022-01-26

REPOSITORIES: Pride

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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.

			Action	DRS
	1988_C1.mgf	Mgf
	1988_C1.raw	Raw
	1988_C2.mgf	Mgf
	1988_C2.raw	Raw
	1988_C3.mgf	Mgf

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Characterization and therapeutic repercussion of the ecology in HER2 positive breast cancer

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