Regulation of ld1 by TGF-beta in breast cancer.

摘要

Breast cancer remains one of the most common types of cancer in women in the developed world. Id proteins are highly expressed in triple-negative breast carcinomas, where they are required for reinitiation of breast cancer lung metastasis. Despite an abundance of data indicating the importance of Id proteins in breast cancer, their precise mechanism of action and equally important, their regulation during breast tumorigenesis remains largely unknown. In this thesis, we address the mechanism of Id1 regulation in breast cancer.;We demonstrate that Id1 expression at the leading edge of primary breast tumors correlates with the activity of the TGF-beta cytokine. TGF-beta has been known to repress Id1 in normal epithelial cells as part of its cytostatic program. However, a dichotomous role for TGF-beta in cancer biology is well established. In breast cancer, TGF-beta has been shown to increase tumor-initiating properties. We show that TGF-beta directly up-regulates Id1 in breast cancer cells and that this effect is specific to cells that have undergone EMT and exhibit mesenchymal morphology. Furthermore, our results indicate that TGF-beta governs tumor-initating potential at least partially through We next explored the mechanism of Idi regulation by TGF-beta. Our results indicate that Idi response is dependent on canonical Smad signaling, specifically Smad3 and Smad4, and requires CBP/p300 co-activators.;Finally, we sought out to analyze the role of ATF-3 and TNF-alpha, known mediators of TGF-beta effects on Idi in epithelial cells. We show that in the context of breast cancer, ATF-3 is negligible for Idi expression, while TNF-alpha acts as an antagonist of TGF-beta mediated induction of Idi.