The BCL-2 Protein BAD in Breast Cancer and Taxane Chemotherapy

• Author / Creator

  Mann, Jasdeep

• Breast cancer is the leading cause of death among women worldwide. Fortunately, death rates have been declining since 1990, due to the increase in early detection, testing, and improved treatment. However, despite the advancement of targeted and hormone therapies for certain molecular sub-types of breast cancer, cytotoxic chemotherapy remains the treatment of choice for patients with hormone receptor-negative tumors, those who are resistant to hormone therapy, or those with aggressive or metastatic disease. Taxanes are a class of anticancer agents that are standard treatment for patients receiving cytotoxic chemotherapy, however, many patients have de novo or acquired resistance. Hence, predicting which breast cancer patients will respond to taxane chemotherapy will circumvent unnecessary toxicity. Our lab has identified the BCL-2 family member BAD as a prognostic indicator of good outcome for breast cancer patients treated with taxane chemotherapy. Therefore, I sought to investigate the function and mechanism of BAD in a breast cancer model to identify how it functions as a biomarker to increase patient responsiveness.
  BAD, classically regarded as a pro-apoptotic protein, binds to anti-apoptotic BCL-2 binding partners at the mitochondria to indirectly activate apoptosis. Upon phosphorylation by survival signaling pathways, BAD is sequestered in the cytosol and bound to regulatory 14-3-3 proteins. Using the phospho-mutant BAD-S118D, I identified a tumor-promoting role of BAD which required binding of 14-3-3. In addition, I discovered BAD over-expression stimulated progression through the cell cycle, leading to increased breast cancer cell proliferation. Although BAD has a known role in stimulating glucokinase activity in pancreatic β-cells and hepatocytes, I discovered a novel role of BAD-mediated regulation of mitochondrial metabolism to promote cell survival. More specifically, BAD cells increased the rate of oxygen flux at complex I of the mitochondria, which was independent of the carbon fuel source. Therefore, I have identified a novel function of BAD in promoting breast cancer cell proliferation and survival in a mitochondrial-dependent mechanism.
  
  Taxanes are anti-mitotic drugs which effectively target actively proliferating cells. Thus, taxanes may elicit an increased response to high-BAD patients because of an increased proliferative index in their tumors. Cell culture and mouse xenograft studies revealed an increased sensitivity to docetaxel in high-BAD cells. Further analysis into the mechanism revealed BAD increased the length of docetaxel-induced mitotic arrest, which was associated with a decreased rate of premature mitotic exit and potential chemotherapeutic resistance. Additionally, I discovered BAD promoted docetaxel-mediated cell death through necroptosis, a programmed form of necrotic cell death. Interestingly, although BAD increased cell proliferation and tumorigenesis, the tumors did not have an aggressive phenotype. They had a reduced cancer stem cell phenotype, were not highly vascularized, and lacked characteristics associated with the ‘Warburg’-effect. These findings suggest high-BAD tumors are not aggressive, but still comprise the features required to increase sensitivity to docetaxel. Thus, BAD functions as a prognostic indicator of good outcome for breast cancer patients treated with taxane due to its inherent function in breast cancer cells and its role in mediating taxane response. Further investigations into its mechanism as a biomarker will advance its utilization in diagnostic testing and in the development of future therapies.

• Subjects / Keywords

  • Taxane
  • Chemotherapy
  • Apoptosis
  • Mitochondria
  • Breast Cancer

• Graduation date

  Fall 2019

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-2172-f452

• License

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