EDUCATING NORMAL BREAST MUCOSA TO PREVENT BREAST CANCER

Project: Research project

Project Details

Description

Despite significant improvements in early detection and treatment of breast cancer, cures remain elusive and overall survival has not improved much over the past eight decades. Going beyond treatment, there has been recent interest in developing prevention strategies. The mammary gland mucosa has an integrated immune system that may function, as it does in the gut, to maintain the epithelial integrity as well as convey protection against microbes. Published studies show that the lack of this immune system predisposes mice to develop mammary adenomas and adenocarcinomas. Our preliminary studies in humans suggest that the absence of a developed mucosal immune system in humans is associated with a higher risk of atypical hyperplasia, a lesion associated with a high risk of developing breast cancer. Based on these data and the known biology of mucosal immune systems, we suspect that we can modify or 'educate' the breast mucosa to deal more effectively with early breast cancer associated lesions, like atypical hyperplasia. In this proposal, we plan to address this hypothesis with these specific aims: (1) to determine the immune cell subsets in normal and hyperplastic breast in murine breast cancer models; (2) to determine whether immunization of mice with tumor antigen modifies the immune cell subsets and leads to persistent trafficking of tumor antigen-specific T and B cells into the mammary gland; and (3) to determine an optimal oral vaccine approach able to minimize hyperplasia. The specific aims will be addressed using transgenic mouse models, BALB/c neu T and B6 neuOT-I/OT-II x DNp53, in which development of breast cancer closely resembles human breast cancer development. In the first step, we will compare the immune effector composition of breast and gut mucosa and determine the effect of different factors that alter mammary gland biology, such as pregnancy hyperplasia, on the immune microenvironment of mammary gland. In the next step by utilizing the information about immune cell subsets profile of mammary gland immune microenvironment, we will determine the ability of intramammary immunization to enhance local immunity in mammary gland. We will also determine the effect of this route of immunization in generating mammary gland resident memory T cell cells and the effect of hyperplasia in altering this population of effector cells. Lastly, the ability of oral vaccination approach by administration of an vaccine encoding target antigens to induce effective local immunity in mammary gland mucosa, suppress the hyperplasia, and inhibit the outgrowth of spontaneous mammary tumors in transgenic mouse models will be determined. Our long-term goal is to develop immune-based approaches (i.e., vaccines) for the prevention of breast cancer, and we expect that data obtained from this proposal would lay the foundation for future studies aimed at this objective.

StatusFinished
Effective start/end date5/1/1211/30/17

Funding

  • Congressionally Directed Medical Research Programs: $771,970.00

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