TGF-â in mammary development and tumorigenesis

Abstract

The transforming growth factor beta (TGF-â) pathway significantly regulates mammary development and tumorigenesis. In human cancer, its signaling pathways are often modified or lost during tumor progression. Prior to initiation and early during progression TGF-â acts upon the epithelium as a tumor suppressor, however at later stages it is often a tumor promoter. This dual role has been previously described as the TGF-â paradox. Importantly, our current studies involving stromal-epithelial and host-tumor interactions, including those presented in this dissertation, are beginning to provide an explanation and mechanisms for the dual nature of TGF-â signaling during tumor progression. The results reported herein, primarily explore the mammary carcinoma cell response to TGF-â signaling and the subsequent impact on the adjacent tumor microenvironment. Notably, we have been able to demonstrate, using two independent parallel model systems, that loss of carcinoma cell specific TGF-â response leads to increased extravascular pulmonary metastasis. In addition, we have shown that the loss of the carcinoma cell specific TGF-â response in primary mammary tumors can result in enhanced carcinoma cell survival, increased adjacent smooth muscle actin positive stroma, increased tumor cell heterogeneity, inflammatory gene expression and inflammation involving bone marrow derived myeloid cells that are known to promote tumor progression and metastasis. To provide mechanisms for these observations, we have performed gene profiling studies with intact or TGF-â signaling deficient carcinoma cells. Importantly, the gene expression profiling results demonstrated regulation of known inflammatory genes by TGF-â and also demonstrated a significant link between the loss of carcinoma cell specific TGF-â signaling and increased risk for relapse in human breast cancer. Together, our results and the current literature, strongly suggest that gain or loss of signaling through the TGF-â pathway in carcinoma cells can promote tumor progression to metastasis though distinct mechanisms in vivo. In addition, if a signature indicative of carcinoma cell TGF-â signaling deficiency is detected in human breast cancer, our results may suggest that the patient should be treated more aggressively to reduce the risk of subsequent relapse and mortality.