Full Project B: Molecular Mechanisms Involved in the Growth and Survival of Bone-Metastatic Breast Carcinoma Cells
Co-Investigators
Edna Mora, M.D., Assistant Professor, Department of Surgery, University of Puerto Rico School of Medicine, San Juan, Puerto Rico
Ana Tari, Ph.D., Assistant Professor, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas
Although the incidence and mortality rates of breast cancer in the Hispanic group is lower compared to whites and African-Americans, the stage at which breast cancer is diagnosed is usually late in the Hispanic group. Therefore, Hispanic patients are at a disproportionately higher risk for metastatic disease at the time of diagnosis. Bone is the most common distant site of metastases in breast cancer patients. So, Hispanic breast cancer patients are more prone to develop bone-metastatic breast cancer disease than white American women. This grant is devoted to understanding the growth and survival mechanisms of bone-metastatic breast cancer. The proposed studies will allow us to identify novel therapeutic targets that could be used to prevent and treat bone-metastatic breast cancer. These studies will be beneficial to Puerto Rican (Hispanic) women, but will also be beneficial to the growing Hispanic population served by MD Anderson. Moreover, these studies will help Dr. Edna Mora as a successful independent investigator in the cancer field. As we know, there is a shortage of independent investigators in minority populations. In addition, surgical oncology has the lowest number of researchers with NIH-supported grants. This effort will help Dr. Mora develop her career and fulfill the lack of Hispanic surgical oncologists in the cancer research field.
Specific Aims
- We will determine whether interleukin-3 (IL-3) stimulates the growth on bone-metastatic breast carcinoma cells (BRCa) via the JAK/STAT pathway and/or Ras and its downstream kinases, such as ERK1, 2, PI3K and Akt. We will assess whether IL-3 can increase the activity of these signaling proteins, and whether inhibition of these signaling proteins will decrease the IL-3-stimulated growth of bone-metastatic BRCa cells
- We will also investigate whether the IL-3 independent growth mechanism is mediated by activation of the epidermal growth factor receptor (EGFR) tyrosine kinase family members, such as EGFR and Her2/neu. We will assess whether activation of EGFR or Her2/neu leads to the activation of JAK/STAT, Ras, ERK1,2, PI3K and Akt. In addition, we will also determine whether inhibition of EGFR or Her2/neu receptors or their signaling proteins could decrease the growth of bone-metastatic BRCa cells
- We will determine whether the survival of bone-metastatic BRCa cells is mediated by the anti-apoptotic proteins Bcl-XL and Bcl-2. Bone-metastatic BRCa cells will be exposed to antisense oligonucleotides specific for Bcl-XL and Bcl-2 so that the protein expression of Bcl-XL or Bcl-2 can be inhibited. We will then expose the bone-metastatic BRCa cells to chemotherapeutic agents, like adriamycin and taxol. We select adriamycin and taxol because both agents significantly increase the survival of breast cancer patients. We will also study the sensitivity of the cells to different types of biophosphonates, as they have been widely used in the treatment of bone-metastatic disease in breast cancer patients. Thus, we choose to investigate the role of Bcl-XL and Bcl-2 in the regulation of the sensitivity of these agents in bone-metastatic BRCa cells. In addition, we will determine whether IL-3 could modulate the sensitivity of bone-metastatic BRCa cells to these agents