Integrin-Mediated Stimulation of HIF-1alpha and Angiogenesis in Breast Cancer

摘要

The work performed during this grant has verified and extended our initial hypothesis. Specifically, we have established that the alpha-6 beta-1 integrin facilitates the survival of breast carcinoma cells in hypoxia by a mechanism that involves its ability to activate HIF-1 and stimulate the transcription of VEGF. The second major discovery made from the work funded by the proposal is that another alpha-6 integrin, alpha-6 beta-4, contributes to the survival of breast carcinoma cells by an entirely different mechanism. This mechanism involves the ability of this integrin to regulate the translation of VEGF through the mTOR pathway. This is a very exciting finding for several reasons. VEGF is probably the tip of the iceberg' and there are likely to be several other proteins important for breast carcinoma survival that are regulated by alpha-6 beta-4 -mediated control of mTOR. Another important aspect of this finding is that mTOR was defined as a target of the drug rapamycin and derivatives of rapamycin are being used with success for adjuvant therapy of breast cancer. Collectively, the work funded by this proposal has revealed the importance of the alpha-6 integrins for the survival of breast carcinoma cells and the mechanisms involved. This work provides a solid foundation for additional mechanistic studies, as well as the potential to exploit the pathways we have highlighted as therapeutic targets.