Breast tumor initiating cells (BTICs), also referred to as cancer stem-like cells, drive breast tumor formation, recurrence, and metastasis. BTICs are largely resistant to chemotherapy and radiotherapy, posing a major obstacle to effective cancer treatment. Therefore, there is an urgent need to develop approaches that would not only destroy the existing BTICs, but would also detect and block the emergence of new BTICs. The long-term goal of our research is to understand how BTICs differ from the rest of breast tumor cells and how this knowledge can be used to develop new anti-BTICs strategies. The objective of this application is to evaluate ADAM12, a member of the ADAM family of cell-surface disintegrin-metalloproteases, as a novel marker and a novel therapeutic target in BTICs. Our central hypothesis is that ADAM12 is specifically induced in BTICs and, by modulating autocrine/paracrine cell signaling, it increases the formation, self-renewal, and/or tumorigenic potential of BTICs. To test our hypothesis, we will pursue the following Specific Aims: 1. Identify mechanisms responsible for the selective up-regulation ADAM12 expression in BTIC-enriched populations of cells. 2. Evaluate ADAM12 as a selective marker for BTICs. 3. Determine the role of ADAM12 in the biology of BTICs. Our studies are significant because they strive to produce new research and diagnostic tools for detection of BTICs and to develop new therapies to target BTICs, which are of critical importance to improve patient survival. The proposed research is innovative because for the first time it takes into account the molecular heterogeneity of breast tumors and new information on the expression pattern of ADAM12 in various molecular subtypes of breast cancer.
The expected outcome of our studies is the identification of a novel marker and/or therapeutic target in breast tumor initiating cells. Therefore, we project that our results will have a significant impact on breast cancer translational research.
|Duhachek-Muggy, Sara; Zolkiewska, Anna (2015) ADAM12-L is a direct target of the miR-29 and miR-200 families in breast cancer. BMC Cancer 15:93|
|Qi, Yue; Duhachek-Muggy, Sara; Li, Hui et al. (2014) Phenotypic diversity of breast cancer-related mutations in metalloproteinase-disintegrin ADAM12. PLoS One 9:e92536|
|Duhachek-Muggy, Sara; Li, Hui; Qi, Yue et al. (2013) Alternative mRNA splicing generates two distinct ADAM12 prodomain variants. PLoS One 8:e75730|
|Li, Hui; Duhachek-Muggy, Sara; Dubnicka, Suzanne et al. (2013) Metalloproteinase-disintegrin ADAM12 is associated with a breast tumor-initiating cell phenotype. Breast Cancer Res Treat 139:691-703|