The p130cas Signaling Axis: Role in Therapeutic Resistance

Ta, Huy Q, Department of Microbiology, University of Virginia
Bouton, Amy, Department of Microbiology, University of Virginia
Shupnik, Peggy, Department of Medicine, University of Virginia
Lannigan, Deborah, Department of Microbiology, University of Virginia
Parsons, Sally, Department of Microbiology, University of Virginia
Silva, Corinne, Department of Microbiology, University of Virginia

Breast cancer continues to be one of the most commonly diagnosed cancers, and the second largest source of cancer death in women in the United States. Despite advances in breast cancer research, there have only been modest improvements in breast cancer specific mortality or in overall survival. Local recurrence and distant metastases are the primary causes of breast cancer-related morbidity and mortality. Resistance to endocrine and chemotherapeutic therapy remains a major obstacle to successful treatment, and ultimately, eradication of cancer. Therefore, understanding the molecular mechanism(s) of resistance is crucial for the development of effective therapies to restore drug sensitivity. High expression of the adaptor molecule p130 Cas (Cas) in primary breast tumors is associated with a failure to respond to the antiestrogen tamoxifen and poor prognosis, highlighting the potential clinical importance of this molecule. However, prior to these studies, an association between Cas and resistance to the chemotherapeutic agent adriamycin had not been established. Studies presented in this thesis show that Cas overexpression induces resistance to the growth-inhibitory and pro-apoptotic effects of adriamycin. Furthermore, Cas promotes resistance through the activation of ERK1/2 and PI3K/Akt signaling pathways, and modulation of the pro-apoptotic Bcl-2 family member Bak. This Cas-mediated resistance requires the kinase activities of c-Src and PI3K. In the iii presence of adriamycin, Cas overexpression induces Bak ubiquitination and degradation through the proteasome, thereby shifting the balance of Bcl-2 family members towards survival. Thus, these data define a novel pathway for regulating drug-induced apoptosis in which the Cas/c-Src/PI3K/Akt signaling axis promotes Bak degradation, significantly reducing its steady state expression level and function. The results described in this thesis have significant implications within the field of cancer therapeutics. Many chemotherapeutic drugs activate apoptotic mechanisms to induce tumor cell death, and factors that impair apoptosis contribute to resistance of tumor cells to cytotoxic chemotherapeutic treatment. Since many traditional anticancer drugs appear to rely largely on Bcl-2 familydependent mechanisms for killing cancer cells, these data presented in this thesis can be used to facilitate the development of novel anticancer therapies and strategies for the prevention of therapeutic resistance of cancers that overexpress Cas.

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PHD (Doctor of Philosophy)
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