Background: Breast cancer cells often display metabolic reprogramming, including enhanced fatty acid (FA) synthesis, which is critical for breast tumorigenesis. Targeting metabolic reprogramming is being actively tested as a novel strategy for cancer therapy and prevention. To identify genes that are critical for breast tumorigenesis, we performed a large-scale in vivo RNAi screen and found that E3 ubiquitin ligase TRIM6 may play an unidentified and critical role in breast tumorigenesis. Currently, the role and mechanism of TRIM6 in breast cancer remain unclear. Our preliminary studies show that (1) TRIM6 expression is downregulated in ~50% of breast cancer and is an early event in breast tumorigenesis. Further, TRIM6 downregulation is associated with poor prognosis in breast cancer; (2) knockdown of TRIM6 promotes growth of orthotopic breast tumors in mice, whereas ectopic expression of TRIM6 inhibited tumor growth; and (3) TRIM6 ubiquitinates and degrades lipogenic enzyme FASN to inhibit FA synthesis in breast cancer. These preliminary results strongly suggest that TRIM6 plays a critical role in suppression of breast tumorigenesis through inhibition of FA synthesis and that decreased TRIM6 expression promotes breast tumorigenesis. Accumulating evidence has shown that vitamin D displays a chemopreventive effect on breast cancer. However, its precise role in breast cancer prevention is not clear, and its underlying mechanism is incompletely understood. Our preliminary results show that vitamin D induces the expression of TRIM6 and inhibits FA synthesis in breast cancer cells. These preliminary results strongly suggest that the induction of TRIM6 expression to inhibit FA synthesis is a critical mechanism whereby vitamin D prevents breast tumorigenesis.Overarching Challenge: This research proposal addresses following two overarching challenges related to breast cancer: (1) identifying drivers of breast cancer growth and (2) breast cancer prevention.Objective/Hypothesis: This research proposal aims to determine the role of TRIM6 in suppressing breast cancer and investigate whether decreased TRIM6 expression promotes breast tumorigenesis. Further, we will determine the role and mechanism of TRIM6 in mediating the function of vitamin D in breast cancer prevention. Based on our preliminary results, we hypothesize that TRIM6 plays an unidentified and critical role in suppression of breast tumorigenesis through inhibition of FA synthesis. We further hypothesize that induction of TRIM6 expression to inhibit FA synthesis is a novel and critical mechanism whereby vitamin D prevents breast tumorigenesis.Specific Aims: Aim 1: To determine the role of TRIM6 in breast cancer in mouse models.Aim 2: To determine the molecular mechanism by which TRIM6 suppresses breast tumorigenesis.Aim 3: To test the hypothesis that TRIM6 mediates the effect of vitamin D in breast cancer prevention.Study Strategy: Aim 1: We will determine the role of TRIM6 in breast tumorigenesis using orthotopic breast tumor models and a conditional TRIM6 knockout mouse model.Aim 2: We will: (a) determine the role of TRIM6 in FA synthesis in breast cancer cells in vitro and in vivo; (b) test whether TRIM6 ubiquitinates and degrades FASN as a key mechanism whereby TRIM6 inhibits lipid synthesis in breast cancer; and (c) determine whether the regulation of FASN by TRIM6 mediates the function of TRIM6 in suppression of breast tumorigenesis.Aim 3: We will: (a) investigate whether vitamin D induces TRIM6 via vitamin D receptor in breast cancer cells; (b) determine whether vitamin D suppresses breast tumorigenesis through upregulating TRIM6 to inhibit FA synthesis in different subtypes of breast cancer cells using orthotopic mouse models; and (c) determine whether TRIM6 mediates the effect of vitamin D in breast cancer prevention by using the MMTV-PyMT preclinical breast tumor mouse model and the conditional TRIM6 knockout mouse model.Impact: Identifying novel drivers for breast cancer and developing novel strategies to target these drivers for breast cancer prevention are highly desirable and urgent. The overall objective of this study is to reveal the unidentified role and mechanism of TRIM6 in breast cancer and determine the role of TRIM6 in mediating the effect of vitamin D in breast cancer prevention. These results will significantly deepen our understanding of the molecular mechanism for tumorigenesis and chemoprevention in breast cancer. Given that the downregulation of TRIM6 is an early and common event in breast cancer, if accomplished successfully, we expect that: (1) TRIM6 levels can be developed as a new and important biomarker to guide the application of vitamin D in chemoprevention and (2) adding vitamin D supplements could be a feasible strategy to prevent breast cancer driven by the loss of TRIM6 expression observed in ~50% of breast cancers, which can be rapidly applicable to chemoprevention. This application will have the direct potential to identify a novel biomarker and develop a novel strategy for personalized breast cancer prevention.
|Effective start/end date||9/1/18 → 8/31/21|
- Congressionally Directed Medical Research Programs (CDMRP)