Phosphatidylinositol 3-Kinase and Protein Kinase C as Molecular Determinants of Chemoresistance in Breast Cancer
Annual summary rept. 1 Jul 2001-30 Jun 2002
TULANE UNIV HEALTH SCIENCE CENTER NEW ORLEANS LA
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The goal of this project is to identify novel therapeutic strategies aimed at counteracting or reversing drug resistance in breast cancer. Chemotherapeutic drug resistance may result, in part, from a shift in the regulation of cellular mechanisms away from apoptosis to a more survival-oriented pathway. Two proteins that have been implicated as anti-apoptotic are protein kinase C and phosphatidylinositol 3-kinase. Although differential expression of these kinases have been linked to anti-apoptotic signaling mechanisms, the molecular details of upstream and downstream events are not well understood, and therefore elucidation of their mechanisms of action may represent a potential therapeutic target for breast cancer. Using an isogenic model system of estrogen receptor positive, apoptosis-sensitive and apoptosis-resistant breast cancer cell variants, this proposal aims to define the role of phosphatidylinositol 3-kinase and specific protein kinase C isoforms in cellular apoptotic signaling pathways. We have found that PKC a and 8 isoforms are differentially expressed in our isogenic model. We are currently optimizing the use of green fluorescent protein-tagged, as well as constitutive-active and dominant-negative, PKC constructs, in order to better understand how PKC and PI3K may affect survival and apoptotic signaling in breast cancer.
- Medicine and Medical Research