Breast cancer is a major disease in the Western world affecting a large percentage of adult women. An effort to find potential chemical agents for the treatment of this disease has been made in many research laboratories. Our studies have focused on a protein called heregulin HRG,which is a factor involved in the growth of the tumor mass as well as in the progression of the breast carcinomas to a more aggressive type of breast cancer. HRG has been shown to induce tumor growth in animal models. Similar to a growing number of growth factors, HRG was also found in the nuclear compartment of breast cancer cells after the cells were treated with HRG, or in cells in which the HRG protein has been expressed. An unexpected facet of this protein has been discovered when cancer cells are treated with HRG, they become more favorably sensitive to some chemotherapeutic drugs. Interestingly, we found that a specific region of HRG sensitizes breast cancer cells to conventional chemotherapy, and moreover that it does not promote the growth of breast cancer cells. We hypothesize that HRG and specific regions of HRGare involved in distinct cellular processes and can be used to develop a universal chemosensitizer. The proposed study will address the possible mechanism responsible for the sensitization function of the HRG protein and its derived mutants on chemotherapeutic drugs. The proposed study will advance our understanding of breast cancer progression and will add new targets for improvements in chemotherapy. The functions of HRG that will be investigated are of great importance to breast cancer treatment, and have not previously been addressed. This study will confirm the novel idea that this protein does not act only as a growth factor as previously asserted, but also, and significantly, as a major player involved in other processes. The experiments that we propose will advance our understanding, and open new avenues for successful chemotherapy of breast cancer.