Probing HER2-PUMA and EGFR-PUMA Crosstalks in Aggressive Breast Cancer.

摘要

EGFR and HER2 are overexpressed in 20% and 30% of invasive breast cancer, respectively, and are associated with aggressive tumor subtypes and shortened patient survival. Both receptors are important targets of breast cancer therapy. However, despite the apparent promise of some of these therapies, EGFR- and HER2-based monotherapy and combination regimens have serious limitations and need improvement. The goal of this study is, thus, to gain insights into the biology of EGFR- and HER2- expressing invasive breast cancer in order to provide rationales for more effective EGFR- and HER2-based combination therapy for women with breast cancer. Our proposal is built on novel significant findings made from the initial Idea Award. We discovered that proapoptotic PUMA protein is highly expressed in the breast cancer cell lines and patient tumors that overexpress HER2 and/or EGFR. In addition to co-expression, we found HER2 and EGFR to interact with PUMA constitutively and under the treatment of apoptosis inducers. The HER2-PUMA and EGFR-PUMA interactions are not disrupted when breast cancer cells are treated with the EGFR kinase inhibitors, indicating a kinase-independent interaction. Despite the fact that PUMA has been reported to be primarily located on the mitochondrial membranes and initiate apoptosis upon appropriate stress, our results showed PUMA to be sequestered in the cytoplasm of EGFR-expressing breast cancer cells. Although, the BH3-only proapoptotic proteins can be functionally redundant, we observed PUMA to be essential for apoptotic induction in breast cancer cells. Interestingly, while no reports have investigated PUMA phosphorylation, our preliminary results show that PUMA undergoes tyrosine phosphorylation mediated by HER2 and EGFR.