UNDERSTANDING FUNCTIONAL BEHAVIORS OF ORGANOTROPIC TRIPLE NEGATIVE BREAST CANCER CELLS

Abstract

11.7% of all cancer cases consist of breast cancer worldwide according to global cancer statistics. Triple negative breast cancer (TNBC) is subtype of breast cancer that has no expression of common hormonal receptors - estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Due to this, TNBC is insensitive to endocrine or molecular targeted therapy and chemotherapy is the most effective treatment. Additionally, TNBC patients have reoccurrence within 3 years of diagnosis. Going further, due to the non-specific targeting of chemotherapy, cancer cells can develop drug resistance. The gold standard does not work in conjunction with microenvironmental factors to reduce disease progression and drug resistance. Not only is this disease lacking in effective treatments but is associated with a health disparity being most prevalent in pre-menopausal and African American women. There is clearlya need to understand the mechanisms of TNBC metastasis because of the impact not only on women in general but on women in historically marginalized communities. A significant innovation in determining cancer treatment is the use of genomic sequencing to identify mutations associated with metastasis. However, tumor heterogeneity puts limitations on fully understanding genomic landscape of TNBC, a highly mutational disease, using sequencing. Further, even when mutations are identified they may not be targetable, or patients may not respond to treatments. While genomic sequencing can be beneficial in improving treatment outcomes, they require further downstream validation of genetic expression to completely understand tumor biology and metastatic progression. This is where understanding the functional behavior of tumor cells with respect to their preferred secondary microenvironment can be advantageous in supplementing genomics data to get a comprehensive understanding of TNBC metastasis. The overall goal of this dissertation is to address this gap by quantifying tumor cell functional behavior and their response to microenvironmental cues. We evaluate three different physical and biochemical behaviors of TNBC tumor cells. In Chapter 3, the effect of TNBC secretome on endothelial barrier properties and function is explored. Chapter 4 quantifies the morphological and migratory phenotypes of brain and bone-seeking TNBC cells in response to ECM protein substrates found in their relevant microenvironments. Lastly, Chapter 5 will quantify the TNBC incorporation in response to brain relevant microenvironmental cues. Quantifying these functional behaviors could provide indicators of brain and bone tropic metastatic behavior and have broader impacts in creating a complete physical profile of organotropic TNBC metastasis.