Breast cancer is one of the most commonly diagnosed cancers among females in United States. Given that we have done little to impact breast cancer deaths, the investigators of the current proposal are of the opinion that the most effective strategy in the long run will be primary prevention. Our long-term objective is to develop immune-based approaches (e.g., vaccines) for the prevention of breast cancer. Although a breast cancer prevention vaccine may seem out of reach, the National Breast Cancer Coalition has identified development of a breast cancer prevention vaccine as the first catalyst project (called Artemis) of focus in their Breast Cancer Deadline 2020 campaign. One of the Principal Investigators of this proposal, Dr. Knutson, was involved in establishing that national project. Recent investigations show that the mammary gland contains, or has the ability to contain, its own immune system. This embedded immune system is distinct from the systemic immune system and appears to have a key role in maintaining and remodeling the epithelial lining of the ducts and lobes. Elimination of this immune system results in an increased risk of benign and cancerous tumors in mice. Humans also have a distinct immune system embedded in their mammary glands. We are proposing in the present study that we can educate the breast's own immune system to get rid of hyperplastic lesions, which are the precursors for cancer. This hypothesis is distinctly different than prior vaccine studies, which are aimed at treating (not preventing) disease and employing systemic vaccines strategies. As the necessary first step toward our goal, we will use breast cancer prone mice to develop a solid foundation of knowledge in the mucosal (i.e., breast associated) immune microenvironment of normal and diseased breast tissues. This will be followed by studies that will evaluate intramammary immunization strategies for preventing hyperplasia. Lastly, we will examine whether an oral immunization approach is effective in preventing hyperplastic lesions. This latter part of the study is proposed because of the well-known link between the mammary gland and the gastrointestinal mucosal immune system (e.g., milk immunoglobulins against intestinal pathogens). It expected that the data derived in the proposed study will begin to address the basic questions that need to be answered with regard to "how to educate the breast mucosa" and provide a foundation for the transition of breast cancer vaccines from therapeutic setting to the prevention setting.
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