Grant: Travel Awards - Institute Community Support

Genetic and clinical studies demonstrate that the Src homology and collagen A (ShcA) adaptor protein is indispensable during breast cancer progression; however the role of the longest isoform (p66ShcA) remains poorly understood. We discovered that p66ShcA is specifically expressed in human basal breast cancer cell lines. Intriguingly, injection of ErbB2-driven breast cancer cells stably overexpressing p66 into the mammary fat pad gave rise to tumors with mesenchymal features relative to vector controls. The epithelial to mesenchymal transition (EMT) endows epithelial cells with mesenchymal characteristics and promotes an invasive phenotype. Indeed, further characterization revealed p66ShcA tumors underwent an EMT distinguished by reduced expression of luminal markers: E-cadherin, claudins 3/4/7, and cytokeratins 8/18 co-incident with increased expression of mesenchymal markers vimentin and smooth muscle actin (SMA). This corresponded with elevated cytokeratin 14 positivity in p66 tumors. Moreover, mRNA expression of EMT-inducing transcription factors: Slug, Twist 1/2 and Zeb 1/2 were significantly elevated in p66ShcA tumors. Corroborating our data, endogenous p66ShcA is upregulated in a novel Met-driven transgenic mouse model of basal breast cancer (MMTV-Met-p53+/-) that undergo an EMT. Notably, we identified activated Met signaling in ErbB2-driven p66ShcA tumors. We hypothesize p66ShcA may elevate Met signaling in order to promote an EMT. Finally, we show that increasing p66ShcA mRNA levels stratify primary breast tumors with elevated EMT markers, independently of breast cancer subtype. Our data provide compelling evidence suggesting that p66ShcA promotes the dedifferentiation of breast tumors by catalyzing an EMT.