Final Report Summary - PTPSBDC (The role of protein-tyrosine phosphatases in breast development and cancer)
Each year, breast cancer is diagnosed in over 1.4 million women worldwide and although the overall survival rates for breast cancer have significantly improved over the decades, more than 500,000 lives are lost to this disease annually. New therapies are likely to arise only from a more thorough understanding of the biology of breast development, cancer and metastasis.
Abnormal tyrosyl phosphorylation enhances breast tumorigenesis but the effects of specific protein-tyrosine phosphatases (PTPs) in breast cancer initiation, maintenance and progression are poorly understood, a question that we investigated. We discovered a key effect for SHP2 in tumor-initiating cells and validated this phosphatase as a target in breast cancer. We also identified the site of action of PTP1B, and addressed the effect of PTPα in breast cancer. In collaboration with other groups we found that PTPN12 is a tumor suppressor in breast cancer. We also showed that PTP1B constrains the number of mammary progenitors and, thus, prevents inappropriate onset of alveologenesis in early pregnancy. Moreover, PTP1B restrains the expression of milk proteins during pregnancy and, thus, prevents premature lactogenesis.
Finally, to develop fidelitous models for studying breast cancer, we have established new cell culture conditions, developed new models of invasive breast cancer, built a bank of normal and neoplastic primary human breast cells and assembled an intravital multiphoton microscope that allows real-time observation of tumor progression in four dimensions (x, y, z and time) and at a single-cell level.