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 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.  We also 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.

Recently, we have identified a role for TGF-beta in regulating the cancer stem cell population, and we have developed a novel fluorescent stem cell reporter which allows us to visualize the cancer stem cell in its native habitat with contextual cues intact. Understanding how TGF-beta modulates cancer stem cell dynamics should give new insights into how to target this therapy-resistant tumor cell subpopulation.