The invasive and metastatic nature of breast cancer poses a formidable challenge due to the associated therapeutic resistance, disease relapse and mortality. The behavior of cancer cells is dictated by their interaction with their surrounding tissue. Osteopontin (OPN) is a critical component of breast stroma. OPN is overexpressed in over 70% cases of malignant breast neoplasms and its overexpression is indicative of poor prognosis. OPN potentiates malignant properties of cells, specifically by promoting their ability to grow, invade, and metastasize. Wnt signaling is dysregulated in breast cancer. We showed that mis-regulation of Wnt homeostasis results in EMT activation and malignant progression. We also demonstrated that DNAJB6, a member of HSP40 family of chaperones, interferes with Wnt/?-catenin signaling and in fact, acts as a gatekeeper of EMT resulting in reduced metastasis. In invasive progression of breast cancer, DNAJB6 protein expression is compromised. Loss of DNAJB6 expression is one of the key factors that promote secretion of OPN by the tumor cells. The central hypothesis of this proposal is that OPN activates Wnt-ligand independent, non-classical ?- catenin signaling, leading to malignant progression of breast cancer. This non-classical activation of ?- catenin activity has profound implications with respect to tumor progression, multi-drug resistance and importantly to Wnt inhibitors being tested in the clinic. Based on compelling observations regarding its ability to counteract Wnt signaling, and restore DNAJB6 expression, we propose to test the dietary flavonoid, fisetin for reversing or preventing EMT and resistance to drug treatment. Fisetin is abundantly present in mangos, strawberries etc. and thus are an affordable means of dietary supplementation. Our objectives are (i) To characterize the mechanisms and effects of non-classical activation of ?-catenin signaling and (ii) To determine if fisetin serves as an effective functional food to revere EMT and prevent metastasis. We will also test fisetin's impact on improving sensitivity of breast cancer cells to cytotoxic chemotherapy. The outcome will allow use of fisetin as a dietary intervention to block non-classical ?-catenin signaling due to OPN in the tumor microenvironment. The work will also test prevention strategies to intervene in metastatic dissemination of breast cancer. Impact: Considering the emphasis of ongoing clinical trials on inhibition of Wnt signaling, the proposed work will have immediate impact on the course of ongoing clinical trials. This research has the potential to complement costly and debilitating chemotherapy regimens.
The proposed research aims to define, treat and prevent the impact of osteopontin in prompting non-classical Wnt signaling, epithelial-mesenchymal-transition and chemoresistance of breast cancer using chemo-dietary intervention.
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