Transcriptional mechanisms regulating oncogenic TGF-β signaling in breast cancer

Abstract

Breast cancer is the most common cancer worldwide in women contributing to 521,000 deaths per year. High mortality rate is due to the occurrence of metastasis, arising from cells that are able to detach from the primary tumor and survive in distant organs where they grow and impair the function of that tissue. It is believed that, although under certain degree of debate, these cells acquire migrative and invasive abilities due to the activation of the cellular program called “epithelial-to-mesenchymal transition” (EMT). This program is activated by aberrant cellular signals. Cellular signals are important to “tell” the cell what it needs to do, produce and degrade among others physiological responses. Every single cell of our body is regulated by and different combination of cellular signals including epithelial cells of the mammary tissue. TGF-β signaling is one important example of this cellular communication, which plays a critical role both during embryonic development and cellular homeostasis of adult body. The activation of this signaling has also been linked to the initiation and maintenance of breast cancer. Activation of TGF-β pathway in mammary epithelial cells is sufficient to change their (epithelial) cuboid polarized morphology of a non-migratory cell towards an elongated-shaped cell with invasive properties, therefore TGF-β is established as a potent inducer of EMT. In this thesis we investigated why signals originated from TGF-β pathway can trigger such malignant alterations on mammary epithelial cells towards cancer. Also, since TGF-β signals have also been shown to maintain cellular homeostasis, we studied which cellular context triggers the loss of tumor suppressive function of TGF-β.