Breast cancer is a major public health problem worldwide. In the United States alone, 178,480 new cases of breast cancer and 40,910 breast cancer deaths were expected in 2007. This unequivocally makes breast cancer the most common cancer in Western women, and second only to lung cancer in terms of cancer morbidity. Alarmingly, the incidence of breast cancer continues to rise with enormous physical, psychological, and social effects on the women who are faced with cancer diagnosis and treatment. During the last decade, great strides have been made in reducing breast cancer morbidity through increased mammography screening coupled with the advent of multi-agent chemotherapy and Tamoxifen. However, treatment of basal-like breast cancer (BLBC) remains especially challenging as these tumours lack the estrogen, progesterone, and HER2 receptors targeted by many traditional chemotherapeutic drugs. Moreover, the tumours readily develop resistance to new generation chemotherapeutic agents, such as Iressa. Further studies are desperately needed to uncover novel signalling cascades responsible for cancer progression that could ultimately be manipulated to combat this highly aggressive subset of breast cancer. The surface of cells are coated with receptors that “listen” to cues from the surrounding environment to direct cells to proliferate, synthesize and excrete proteins, or even undergo apoptosis (cell death). Traditionally, it was believed that these signals were sent to the cell nucleus exclusively through complex and elaborate cascades of intracellular messengers. However, it has recently emerged that cell receptors can become internalized and trafficked to the nucleus where they can act as transcription factors – in essence proteins that can turn on and off particular genes. This novel pathway has tremendous consequences for cancer biology as it offers a novel mechanism which cancerous cells could be exploiting to proliferate, metastasize (spread to other sites), to even combat the effects of chemotherapy. I have recently demonstrated that a fragment of the epidermal growth factor receptor (EGFR) translocates from the cell surface to the nucleus in BLBC cells. This is an exciting finding because EGFR is overexpressed in 50% of BLBCs, but more importantly, it could explain why these cells are resistant to Iressa, a chemotherapeutic that inhibits EGFR from sending messages via signal transduction cascades. Specifically, a fragment of the receptor could be cleaved to directly activate pro-survival genes in the nucleus. My research proposal is focused on gaining a more in depth understanding of this novel, cleaved form of EGFR, known as nuclear EGFR. Specifically, I am interested in determining the structure of nuclear EGFR and uncovering if it interacts with other proteins in the nucleus. In addition, I want to discover the specific pro-survival genes that are being induced by nuclear EGFR. This work will determine if targeting nuclear EGFR represents a viable strategy for combating cell proliferation, metastasis, and therapeutic resistance in a subset of cancer where treatment options are currently limited.