Abstract A38: Breast cancer intrinsic subtype specific interactions with the microenvironment dictate the mechanism of tumor invasion

Breast cancer patient mortality is a consequence of the metastatic dissemination of neoplastic cells into foreign tissues, not the primary tumor growth. Fibroblasts located in the breast microenvironment may trigger neoplastic cells to invade out of the mammary duct and into the stroma, an early step in breast cancer metastasis. Investigating how mammary fibroblasts promote breast cancer invasion may improve both treatment and the accuracy of diagnosis of breast cancer patients. To elucidate the mechanism of tumor cell invasion, we use organotypic cultures to generate three-dimensional interactions between breast cancer cells and the microenvironment and xenograft models for our in vivo studies. Live cell imaging, immunofluorescence and other biochemical methods were used to determine the interaction between breast cancer cells and mammary fibroblasts. We have found that mammary fibroblasts specifically induce the invasion of basal-type breast cancer cells. The propensity of the mammary fibroblasts to induce the invasion of the basal-type breast cancer cells correlated with the reorganization of the collagen in the microenvironment. Secreted factors from the mammary fibroblasts were insufficient to induce invasion of the neoplastic cells. Instead, we discovered that the Cdc42 dependent reorganization of stromal collagen by the mammary fibroblasts was necessary for the induction of basal-type breast cancer cell invasion. To determine how the basal-type breast cancer cells opportunistically invaded into paths created in the stromal collagen, we imaged an organotypic culture model in real-time. The live-imaging revealed that basal-type breast cancer cells within spheroids were motile and constantly exchanging cell-to-cell partners within the confines of the sphere. In contrast, the luminal-type breast cancer cells were not motile within the spheroids. When co-cultured with mammary fibroblasts, the basal-type breast cancer cells that invaded through paths created in the collagen were motile cells. The static luminal-type breast cancer cells were not able to leave the spheroids and invade into the stroma. Thus, the intrinsic ability of the basal-type breast cancer cells to move within multicellular spheroids promoted the invasion in response to the accumulation of nearby mammary fibroblasts. Cell motility is a complex process with many regulatory components including microRNA dependent control of gene expression. Expression profiling of patient and breast cancer cell lines has demonstrated that there is differential microRNA expression between the basal and luminal breast cancer subtypes. We are currently exploring how intrinsic subtype specific microRNA expression contributes to the differential motility observed between the basal and luminal-type breast cancer cells. In conclusion, our data suggest that mammary fibroblasts are sufficient to induce motile basal-type breast cancer cells to invade into the stroma and we are investigating how basal-type breast cancer microRNA expression promotes cell motility. Citation Format: Tuyen T. Dang, Gray W. Pearson. Breast cancer intrinsic subtype specific interactions with the microenvironment dictate the mechanism of tumor invasion. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A38.