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Targeting Breast Cancer Recurrence via Hedgehog-mediated Sensitization of Breast Cancer Stem Cells
Annual rept. 15 Jun 2010-14 Jun 2011
MIAMI UNIV FL
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The purpose of the research supported by this award is to determine if targeting the hedgehog signaling pathway in breast cancer can reduce breast cancer recurrence. Two specific facts about breast cancer recurrence highlight the need for better treatment modalities that target and prevent disease recurrence. 1. In the United States and other countries with access to advanced cancer care, local and distant breast cancer recurrence accounts for 95 of breast cancer mortalityJemal et al., 2010. 2. The life-time risk of breast cancer recurrence among survivors is greater than the lifetime risk of developing breast cancer in the general populationJemal et al., 2010. Together these two statements suggest that while substantial progress has been made in treating primary breast cancer, those treatments do not efficiently reduce the risk of disease recurrence. Therefore there is a need for novel treatment strategies. Disease recurrence is believed to be the result of a subset of tumor cells with two distinct features broad spectrum resistance to therapeutics and tumorigenicityHurt and Farrar, 2008 Pardal et al., 2003 Polyak and Weinberg, 2009 Woodward et al., 2005. Our previous studies identified a regulatory relationship between Np63 a protein that is required for long-term preservation of epithelial stem cellsMills et al., 1999 Yang et al., 1999 and the hedgehog-signaling pathway that governed stem cell quiescenceLi et al., 2008. Stem cell quiescence is necessary to preserve long-term replicative capacity while simultaneously avoiding the detrimental effects of excessive proliferation. It is also a potent blockade to cellular differentiationColler et al., 2006. Based upon this we put forth the hypothesis that the hedgehog signaling pathway could be targeted to subvert quiescence in stem cell populations. Doing so would force these cells back into the cell cycle, thereby sensitizing them to adjuvant cancer therapeutics.
APPROVED FOR PUBLIC RELEASE