Role of the type III TGF-beta receptor cytoplasmic domain in breast cancer progression

Breast cancer remains among the most common cancers of the developed world. Despite advances in treatment modalities, deaths due to breast cancer are the second leading cause of cancer death among women. The transforming growth factor-beta (TGF-beta) pathway is an important modulator of breast cancer progression, acting in a tumor suppressing fashion in early carcinogenesis but switching in a poorly understood fashion to a promoter of cancer progression in later stages. Mutations and loss of function of TGF-beta components are common across a variety of cancers. In particular, the expression of the type III TGF-beta receptor (TbetaRIII) is decreased with cancer grade and clinical progression in prostate, lung, ovarian, and pancreatic cancers. In an effort to enhance our understanding of the biology of TGF-beta on carcinogenesis, this dissertation looks at the role of TbetaRIII in breast cancer progression.;Through an examination of clinical specimens, loss of TbetaRIII was seen at both the message and protein levels with increasing tumor grade. Analysis of correlated patient outcomes showed that low TbetaRIII expression was predictive of a shorter time to recurrence, demonstrating clinical relevance for TbetaRIII expression. The contribution of TbetaRIII to tumor progression was further examined by examining known TGF-beta functions, including proliferation, apoptosis, migration, and invasion. TbetaRIII had no effect on proliferation or apoptosis, but had a suppressive effect on metastasis in vivo, as mammary cancer cells stably expressing TbetaRIII that were orthotopically injected exhibited lower metatstatic burden and local invasion. In vitro, breast cancer cells exhibited suppression of migration and invasion in transwell assays. Finally, soluble TbetaRIII (sTbetaRIII) was shown to recapitulate the suppressive effects on invasion.;To further explore other potential mechanisms by which TbetaRIII may be mediating its tumor suppressive effects, I examined the contribution of the cytoplasmic domain of TbetaRIII, which is known to be critical in the regulation of TbetaRIII cell surface expression and downstream signaling. In vitro, I demonstrated that abrogation of the cytoplasmic domain attenuates the TbetaRIII-mediated suppression of migration and invasion. TbetaRIII's suppressive effects are also concomitant with loss of TGF-beta signaling, as abrogation of the cytoplasmic domain failed to attenuate TGF-beta signaling while the full length receptor was able to do so. In vivo, I also showed that in the absence of the cytoplasmic domain, TbetaRIII is unable to suppress metastasis and local invasion. Finally, a closer dissection of the cytoplasmic domain revealed that abolishing the interaction of TbetaRIII with the scaffolding protein GIPC also attenuated TbetaRIII's ability to dampen TGF-beta signaling and invasion.;In sum, TbetaRIII was established as a prognostic marker for recurrence-free survival of breast cancer patients and as a suppressor of metastasis, migration, and invasion. Furthermore, several mechanisms contribute to TbetaRIII's tumor suppressive effects, namely the generation of sTbetaRIII and the interaction of TbetaRIII with GIPC. Taken together, these studies further demonstrate the importance of TGF-beta signaling in cancer biology, elucidate mechanisms by which TbetaRIII suppresses breast carcinogenesis, and expand upon our understanding of the emerging roles of TbetaRIII in regulating tumor biology in general.