Characterization of metastasis models derived from breast cancer patients of African descent

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Project Summary: Breast cancers arise in one out of eight women and account for ~40,000 deaths each year in the United States. There are different types of breast tumors with varied treatment options and outcomes. Triple-negative breast cancers (TNBC) lack estrogen and progesterone receptors (ER and PR), do not express the HER2 oncogene, and are known to be highly metastatic. Since they lack ER, they cannot be targeted with antiestrogens, and by not having amplified HER2, the drugs that target this protein are ineffective. People that are of African ancestry (AA) are two-to-three times as likely to be diagnosed with basal-like TNBC than people of European ancestry, which is a major disparity and contributes to a significantly poor prognosis. Given that genetic factors have been identified which portend poor outcomes in AA patients, we hypothesize that AA derived tumor cells have unique susceptibilities which can be exploited for therapeutic benefit. The goal of this R21 project is to refine metastasis models systems derived from people of AA as they are currently lacking in abundance and determine novel therapeutic options that may best benefit them. The proposal will (1) develop trackable metastasis models from AA TNBC patient-derived xenografts, (2) define their organ tropism, (3) genomically characterize them at the single-cell level, and (4) identify and test therapeutics which may be beneficial in addition to standard of care chemotherapeutics. The study is innovative through its multifaceted approach and significant as it will directly address a major disparity and provide options for expanded testing of therapeutics that could be utilized in the clinic immediately. The expected outcome of these efforts is that we will develop model systems that can be shared with the broader research community and identify genomic features that are activated in metastases and can be targeted. Achieving these goals will have a positive impact on disparities research and breast cancer treatment.