Targeting Cell Polarity Machinery to Exhaust Breast Cancer Stem Cells

Abstract : Cancer stem cells (CSCs), a cell population with acquired perpetuating self-renewal properties which resemble normal stem cells, specifically in the ability to infinitely give rise to the bulk of a tumor as the seed of the cancer, account for cancer initiation, progression, recurrence, and chemo-resistance. The cell polarity machinery has been strongly suspected of playing an evolutionarily-conserved role in regulating the cell fate in both normal and neoplastic stem cell populations, which suggests that therapeutic targeting of this mechanism may be an effective strategy for eliminating CSCs and thereby impeding cancer progression and recurrence. During the first grant period, we have successfully completed the proposed studies in Aim1 and have also made significant progress in the ongoing experiments in Aim2. Our results collectively support the hypothesis that PKCzeta is a novel target of microRNA-200c (miR-200c), the most significantly down-regulated miRNA in breast CSCs. Dysregulation of miR200c-PKCzeta signaling is critical for sustaining a self-renewing breast CSC pool and is associated with high-grade aggressive breast cancer. Together, these data point to a great potential for the strategies targeting PKCzeta signaling to exhaust the CSC pool for treatment of breast cancer.