| dc.description.abstract | Enhanced expression of CXCL1 in tumor epithelium is associated with cell invasion and angiogenesis in melanoma, bladder, ovarian and breast cancer, yet CXCL1 expression in tumor associated stroma is largely undefined. In this dissertation, we show evidences that increased CXCL1 expression in breast cancer stroma correlates with poor patient prognosis, including increased rate of recurrence and shorter relapse-free survival, and co-localizes to alpha Smooth Muscle Actin (-SMA) and Fibroblast Specific Protein 1 (FSP1) positive fibroblasts. Fibroblasts are important cellular components of the breast tumor microenvironment, and their accumulation correlates with invasive cancer progression and poor patient prognosis. However, the understanding of functional contribution of fibroblast secreted factors to breast tumor progression still remains limited. In this dissertation, we demonstrate that breast cancer associated fibroblasts (CAFs) overexpress CXCL1, which promotes luminal and basal-like breast cancer cell survival, invasion and mammary tumor progression through CXCR2-dependent mechanisms in vitro and in vivo. By candidate profiling, we have found the TGF- signaling pathway as a regulator of CXCL1 expression in mammary fibroblasts. Mechanistically, we show that TGF- suppresses CXCL1 expression through Smad2/3-dependent mechanisms, and, as a secondary mechanism, TGF- suppresses CXCL1 expression through down-regulation of HGF/c-Met signaling. In summary, we document the prognostic relevance and significance of CXCL1 protein expression in breast cancer stroma, characterize the molecular mechanisms of CXCL1 expression in mammary fibroblasts in the context of TGF- signaling, and demonstrate the functional contribution of fibroblast-derived paracrine CXCL1/CXCR2 signaling in mediating breast cancer cell survival, invasion and tumor progression. | |
