Breast cancer metastasis is responsible for more than 90% of cancer death in women and is thought to be caused by breast cancer stem cells that are often located in regions without sufficient oxygen supply (a phenomenon known as hypoxia). Hypoxia-inducible factor (HIF) is a master regulator frequently detected in the hypoxic regions and controls cellular responses to hypoxia. Previous studies have shown that HIF is critical for breast cancer stem cells to survive and spread around the body. However, the precise mechanism by which hypoxia/HIF regulate breast cancer stem cells to promote breast cancer metastasis remains unknown. We recently discovered ZMYND8, a protein that is highly expressed...

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Breast cancer metastasis is responsible for more than 90% of cancer death in women and is thought to be caused by breast cancer stem cells that are often located in regions without sufficient oxygen supply (a phenomenon known as hypoxia). Hypoxia-inducible factor (HIF) is a master regulator frequently detected in the hypoxic regions and controls cellular responses to hypoxia. Previous studies have shown that HIF is critical for breast cancer stem cells to survive and spread around the body. However, the precise mechanism by which hypoxia/HIF regulate breast cancer stem cells to promote breast cancer metastasis remains unknown. We recently discovered ZMYND8, a protein that is highly expressed in breast cancer stem cells in response to hypoxia and predicts poor survival of patients with breast cancer. ZMYND8 protein induces HIF-dependent pluripotency-associated genes and increases the activity of breast cancer stem cells under hypoxia. We also found that ZMYND8 protein contributes to breast tumor growth and metastasis in mice. The goal of this proposal is to understand the mechanism of ZMYND8 protein in maintaining breast cancer stem cells and subsequent breast tumor metastasis. Using a combination of biochemical and genetic approaches, we will (1) determine the role of ZMYND8 in HIF-dependent stemness of breast cancer stem cells and breast cancer metastasis, and (2) dissect the mechanism of ZMYND8-mediated maintenance of breast cancer stem cells. Successful completion of the proposed project will contribute to understanding the cause of breast cancer metastasis at the molecular levels, and yield a possible molecular target for the treatment of metastatic breast cancer. Overall, we hope that the proposed research will provide a solid foundation for the development of new approaches for breast cancer therapy, leading to the reduction of this very aggressive and deadly disease.

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