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Binwu Tang, Ph.D.
Dr. Tang's major research interest is focused on understanding molecular mechanisms the dual role of TGF-beta in breast cancer. Dr. Tang formally tested the hypothesis that TGF-beta can switch from tumor suppressor to prometastatic factor during the course of carcinogenic progression within a given cell lineage. We used a xenograft model system of breast cancer progression, based on the MCF10A human breast epithelial line and transformed derivatives. By transducing these cells with a dominant negative form of the TGF-beta receptor and testing for tumorigenicity in nude mice, we have determined the dominant role played by the endogenous TGF-beta system at the various different stages. We have shown that decreased TGF-beta responsiveness alone cannot initiate tumorigenesis, but that it can cooperate with an initiating oncogenic lesion to make a premalignant breast cell tumorigenic and a low-grade tumorigenic line more aggressively tumorigenic. However, in a high-grade tumorigenic cell line, reduced TGF-beta responsiveness has no effect on primary tumorigenesis, but significantly reduces metastatic efficiency. Our results demonstrate a causal role for loss of TGF-beta response in promoting breast cancer progression up to the stage of advanced, histologically aggressive, but non-metastatic disease, and suggest that at that point TGF-beta switches from tumor suppressor to pro-metastatic factor. Recently, we showed that endogenous TGF-beta has the potential to suppress tumorigenesis through a novel mechanism, involving effects at two distinct levels in the hierarchy of cellular progeny that make up the epithelial component of the tumor. First, TGF-beta reduces the size of the putative cancer stem or early progenitor cell population, and second it promotes differentiation of a more committed, but highly proliferative, progenitor cell population to an intrinsically less proliferative state. We further show that reduced expression of the type II TGF-beta receptor correlates with loss of luminal differentiation in a clinical breast cancer cohort, suggesting that this mechanism may be clinically relevant. At a molecular level, the induction of differentiation by TGF-beta involves down-regulation of Id1, and forced overexpression of Id1 can promote tumorigenesis despite persistence of the antiproliferative effect of TGF-beta. These data suggest new roles for the TGF-beta pathway in regulating tumor cell dynamics that are independent of direct effects on proliferation.
This page was last updated on 3/5/2013.