Abstract 4027: Aggressive breast cancer associated fibroblasts communicate with cancer cells via microRNAs and promote an aggressive breast cancer phenotype
Authors: Shah Sanket , Ao Zheng , Miller Philip , Dattar Ram , Lippman Marc , El-Ashry Dorraya 
Published: August 2015

Background: Increasing evidence has demonstrated that stromal cells play a pivotal role to promote breast cancer progression and metastasis. Breast cancer stroma is comprised mainly of Cancer Associated Fibroblasts (CAFs). Upon interaction with tumor cells CAFs are known to promote tumor progression by providing paracrine oncogenic signals mediated by activation of various pathways including developmental pathways, integrin signaling, and MAPK pathway in tumor cells. CAFs have also been shown to promote the survival of CTCs and help them in metastasis at distant sites. Using breast cancer patient tumor datasets, we have previously identified a microRNA signature reflective of hyperactive MAPK signaling and that is significantly associated with reduced recurrence-free and overall survival, and response to hormone therapy in ER+ patients. Breast tumors from the TCGA and METABRIC breast cancer datasets classified as high hMAPK-miRNA exhibit signficant stromal and immune cell infiltrate, suggesting that these cell types may contribute to the hMAPK-miRNA signature. We have established primary breast CAF lines, from different breast cancer subtypes, along with several primary tumor-derived dissociated tumor (DT) culture models that are tumorigenic in vivo and vary in metastatic ability, and have found that the CAFs differentially express several hMAPK-microRNAs compared to the DTs.

Results: To investigate the role of specific expression of hMAPK-miRNAs secreted by CAFs, CM was isolated from CAFs from “aggressive” tumors (TNBC), from “indolent” tumors (ER+, luminal A), and from normal human mammary fibroblasts (HMFs) and analyzed for exosome and microRNA secretion. CAFs from the aggressive tumors showed an overexpression of various secreted hMAPK-microRNAs into the CM than do HMFs or CAFs from indolent tumors. Several hMAPK microRNAs were secreted by “aggressive” CAFs compared to “indolent” CAFs or HMFs, including miR221/222. The secreted miR221/222 could down-regulate both ER and TRPS1 (a negative regulator of EMT), known targets of miR221/222, in MCF-7 breast cancer cells. The hMAPK-regulated miR155 is also secreted by “aggressive” CAFs, and regulates Myeloid derived suppressor cell induction To determine if the secreted miRNA differences exhibited by the different CAFs could be seen in patients, serum from breast cancer patients with metastatic breast cancer and patients without metastases was analyzed for microRNA expression. Differentially expressed circulating miRNAs were identified in serum from metastatic breast cancer patients compared with patients without metastatses.

Conclusion: Together, these data suggest that CAFs from aggressive tumors supports the aggressive breast tumor phenotype by repressing ER, facilitating EMT and helping tumor cells escape immune surveillance.

Citation Format: Sanket Shah, Zheng Ao, Philip Miller, Ram Dattar, Marc Lippman, Dorraya El-Ashry. Aggressive breast cancer associated fibroblasts communicate with cancer cells via microRNAs and promote an aggressive breast cancer phenotype. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4027. doi:10.1158/1538-7445.AM2015-4027