The Role of TRIM6 in Breast Cancer Metabolism and Cancer Prevention

  • Feng, Zhaohui Z (PI)

Project Details

Description

Breast cancer remains to be one of the most common cancers and a leading cause of cancer-related death in women despite significant advances in screening approaches, allowing for early detection of the disease, as well as continuous evolution of targeted therapies. Identifying novel drivers for breast cancer development and developing novel and effective strategies to target these drivers for breast cancer prevention are highly desirable and urgent, which will significantly impact the field of breast cancer prevention. This research proposal aims to address following two overarching challenges related to breast cancer: (1) identifying drivers of breast cancer growth and (2) breast cancer prevention. Using a large-scale unbiased RNA interference screen in preclinical mouse models, our preliminary studies identified E3 ubiquitin ligase TRIM6 as an unidentified and critical player in breast cancer. Currently, the role and mechanism of TRIM6 in breast cancer remain unclear. Our preliminary studies showed that the downregulation of TRIM6 expression is frequently observed in breast cancer (in ~50% of breast cancer), which is an early event in breast tumorigenesis. TRIM6 downregulation is associated with poor prognosis in breast cancer. Our preliminary results further suggest that TRIM6 plays a critical role in suppression of breast cancer through inhibiting fatty acid synthesis, a metabolic change that contributes to breast tumorigenesis and that downregulation of TRIM6 expression promotes breast tumorigenesis. Accumulating evidence has strongly suggested that vitamin D displays a chemoprevention effect on breast cancer and that adding vitamin D supplements is an economical and safe way to reduce breast cancer incidence. However, epidemiological studies and clinical trials have not produced consistent results to support the chemoprevention effect of vitamin D on breast cancer. The different levels and activities of regulating proteins and/or effector proteins of vitamin D in human populations and cancer patients could be an important reason for these inconsistent results. Therefore, identifying these proteins to understand the mechanism underlying the chemoprevention effect of vitamin D will significantly improve the chemoprevention efficacy of vitamin D and help to identify the populations and breast cancer patients that will benefit from the anticancer effect of vitamin D. Our preliminary results strongly suggest that TRIM6 plays a critical role in mediating the anti-cancer effect of vitamin D in breast cancer; vitamin D induces TRIM6 to suppress breast tumorigenesis. In this proposed study, we will employ human breast cancer cells and preclinical breast cancer mouse models to: (1) determine the role and mechanism of TRIM6 in breast cancer; (2) determine whether decreased TRIM6 expression drives breast tumorigenesis; and (3) determine the role and mechanism of TRIM6 in mediating the effect of vitamin D in breast cancer prevention. The overall objective of this study is to reveal the unidentified role and mechanism of TRIM6 in breast cancer, and determine the role and mechanism of TRIM6 in mediating the effect of vitamin D in breast cancer prevention. We anticipate that results from this study will identify decreased TRIM6 expression as an important driver for breast tumorigenesis, which will significantly improve our understanding of the molecular mechanism of breast cancer. Further, we anticipate that our results will identify TRIM6 as a critical mediator for the chemoprevention effect of vitamin D in breast cancer. These results will have a potential to resolve the inconsistent results on vitamin D in breast cancer prevention. Given that the downregulation of TRIM6 is an early and common event in breast cancer, if accomplished successfully, we expect that: (1) the TRIM6 level can be developed as an important biomarker to guide the application of vitamin D in chemoprevention of breast cancer and (2) addi

StatusActive
Effective start/end date9/1/18 → …

Funding

  • U.S. Army: $1,192,500.00

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