Targeting Breast Cancer Recurrence via Hedgehog-Mediated Sensitization of Breast Cancer Stem Cells
Abstract
Research supported by this award aims to determine if targeting the hedgehog signaling pathway in breast cancer can reduce breast cancer recurrence. 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 mortality. Additionally, t he life-time risk of breast cancer recurrence is greater than the life-time risk of developing breast cancer in the general population. Together these two statements indicate that current treatments do not efficiently reduce the risk of disease recurrence. Disease recurrence is believed to be the result of a subset of tumor cells with two distinct features; broad-spectrum resistance to therapeutics and tumorigenicity. Our previous studies identified a regulatory relationship between Np63 a protein that is required for long-term preservation of epithelial stem cells and the hedgehog-signaling pathway that governed stem cell quiescence. 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 differentiation. 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, possibly sensitizing them to adjuvant cancer therapeutics. To test this hypothesis we developed three specific tasks that are described in detail in the Statement of Work. Since this award was a collaborative IDEA award we sought to take advantage of the hedgehog-signaling expertise of Dr. David J. Robbins and the mammary stem cell and breast cancer expertise of Dr. James DiRenzo. What follows is a detailed description of progress towards the completion of the research supported by this award.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2011
- Accession Number
- ADA560850
Entities
People
- James Direnzo
Organizations
- Dartmouth College