Multipotential Mesenchymal Stromal cells (MSCs) hold great potential for treating human degenerative diseases and injuries. Recent, studies regarding the biology of breast cancer stroma indicate that mesenchymal stem cells (MSCs) provide the supportive stroma for breast tumors. However, there is a significant gap in our understanding of the survival mechanisms used by stromal cells under stressful conditions normally observed within solid tumors, such as hypoxia or nutrient deprivation. Most of the currently available therapeutic strategies only target the cancer cells and not the tumor-associated stroma. Indeed, a more detailed understanding of the molecular mechanisms involved in MSC survival and the resultant stromal supportive functions, is essential for improving the design and selection of therapeutic targets against breast cancer. In this study, properties of a MSC subpopulation that survive serum deprivation and express primitive characteristics will be used as model to understand role of stromal cells in breast cancers especially during adverse conditions such as hypoxia or nutrient deprivation. The serum deprived MSCs (SD-MSCs) utilize autophagy to survive and secrete survial factors such as IGF-1, TGFb etc that support breast cancer cells. Autophagy is an essential part of growth regulation maintenance of homeostasis in multicellular organism. MicroRNAs (miRNAs) are evolutionary conserved; short non-coding regulatory RNAs that post-transcriptionally modulate gene expression of a variety of genes including oncogenes and tumor suppressors, as well as those regulating cell survival and growth. Drosha and Dicer are important enzymes required for miRNA biogenesis. The miRNAs function by binding to a cognate targets mRNA and facilitates their specific degradation. Our preliminary data uncovered a novel mechanism of linking SD-MSC survival to miRNA regulation, in addition to demonstrating that loss of drosha and dicer function abrogates differentiation in MSCs. The overall goal of this proposal is to understand the role of miRNAs in regulating the survival of tumor-associated stromal cells and in enhancing their supportive function/s towards breast cancer cell growth. The specific hypothesis for this study is the tumor-stroma can survive stressful conditions of the tumor microenvironments by differentially regulating expression of specific miRNAs, and targeting of these miRNAs within the tumor-stroma will abrogate their facilitative effects on breast cancer development and progression. To achieve this goal the following aims are proposed (1) To determine whether a specific miRNA expression profile is associated with the survival of MSCs under stressful conditions in vitro. (2) To investigate the role of stressed stromal cells, and the associated miRNA pathways, in facilitating the stromal supportive functions towards breast cancer cell growth. (3) To delineate the miRNAs that play a role in survival of MSCs and identify those which can be targeted as novel anti-cancer strategies. The experiments proposed here to study the role of miRNA pathway in the stromal cell support will be important to understand how stromal cells survive under adverse conditions and support the tumor cells surrounding them. In addition, novel therapeutic targets to abrogate stromal cell survial will be indentified.
This study will give us insight into the potential role that mesenchymal stem/progenitor cells have in the stromal support of breast cancers. It will also lead to identification of miRNA targets that are involved in the survival of stromal cells under stress and chemotherapeutic drugs. Identification of molecular pathways involved stromal cell survival may lead to identification of new therapeutic targets for resistant breast cancer.
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