Molecular mechanisms in growth/survival of bone metastatic breast carcinoma cells

University Of Texas Md Anderson Can Ctr, Houston TX

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Abstract

Breast cancer is the most common malignancy of women in Puerto Rico and North America. Bone is the most common distant site of metastasis in breast cancer patients from all ethnic groups. Only palliative treatment is available to treat these patients. Breast cancer is usually diagnosed at a late stage in minority populations. Therefore, the incidence of bone-metastatic disease in breast cancer patients from minority populations is higher than in the general breast cancer population. The mechanisms by which breast cancer cells from the primary site selectively colonize and grow in the metastatic site are still unknown. We have preliminary data indicating that interleukin-3 (IL-3) selectively enhances the growth for bone-metastatic, but not pleural-metastatic, breast carcinoma (BRCA) cells. Our preliminary data led us to hypothesize that bone-metastatic BRCa cells use IL-3 mediated as well as IL-3 independent mechanisms to promote their growth and survival at this metastatic site. Furthermore, we hypothesize that increased expression of anti-apoptotic proteins, like Bcl-2 and Bcl-XL, enhance the survival of bone-metastatic BRCa cells. We will determine whether the IL-3 dependent and- independent growth mechanisms of the bone metastatic BRCa cells involve JAK/STAT, and Ras and its downstream kinases. We will also determine whether the EGFR and Her2/neu tyrosine kinases are the IL-3 independent mechanisms that regulate the growth of bone-metastatic BRCa cells. Finally, we will also determine whether bone-metastatic BRCa cells use the anti-apoptotic proteins, such as Bcl-XL and Bcl-2 to, increase their survival against biphosphonates and chemotherapeutic agents (Adriamycin, Taxon), and whether the expression of these anti-apoptotic proteins are regulated by IL-3. These studies will further our understanding of the mechanisms by which bone-metastatic BRCa cells increase cell growth and survival, and may allow us to identify novel therapeutic targets for the effective prevention and treatment of bone metastatic disease in breast cancer patients.