Interactions between ES-miRNAs and environmental risk factors are responsible for TNBC progression and associated racial health disparities: a novel analysis with multilevel moderation inferences

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Project Summary: For women in the United States, breast cancer is not only the most common malignancy but also the second leading cause of death. In this application, we focus on a specific subtype of breast cancer known as triple- negative breast cancer (TNBC). Because TNBC has a higher recurrence rate and poorer overall mortality than other subtypes of breast cancer, it is more aggressive and extremely difficult to treat with standard therapies. Epidemiological studies have clearly shown that African American (AA) women are more likely to develop advanced TNBC than Caucasian American (CA) women. For instance, in Louisiana (LA), where we live, from 2010 to 2017, there were 3,790 TNBC cases, of which 1,861 (49.1%) were from the AA population versus 1,900 (50.1%) were from the CA population, while 32.8% of the LA population were AA and 62.8% were CA. Notably, 43.5% of the AA patients were diagnosed with regional or distant metastasis, compared with 36.6% of CA patients. Thus, TNBC represents a significant challenge to racial health disparities in Louisiana. The overall goal of this project is to determine the extent to which modifiable factors in the neighborhood physical and social environment affect the prognosis of TNBC patients and whether their effects can be accurately reflected and quantified through detectable biological variables. Recent studies have revealed that tumor-derived exosomes (TDEs) play a prominent role in promoting tumor progression and metastasis. TDEs contain many oncogenic elements, including multiple miRNAs, mRNAs, proteins, and lipids. Notably, exosomal miRNAs (ES-miRs) have been reported to be critical for crosstalk between tumor cells and stromal cells in the tumor microenvironment (TME) and the establishment of pre-metastatic niches. Therefore, we hypothesize that ES-miRs are biological variables that not only reflect and quantify the effects of environmental risk factors associated with racial health disparities, but are also functionally involved in the progression of TNBC. Our specific aims are as follows: Aim 1: Use multilevel mediation and moderation analysis to identify significant ES-miRs and environmental risk factors for TNBC progression and understand how their interactions explain racial health disparities in TNBC. Aim 2: Validate the function of selected ES-miRs in TNBC progression using in vitro and in vivo models. Aim 3: Develop a new model to predict TNBC progression in AA and CA patients. We expect that our study can develop an innovative approach to quantify adverse physical and social environmental influences on the progression of TNBC across different races and provide insights into the development of more effective strategies to reduce racial health disparities in TNBC.