In the United States it is estimated that over 207,000 women were diagnosed with breast cancer, and nearly 40,000 women died of the disease in 2010 (NIH-SEER database). Mortality from breast cancer is almost always attributed to the distant spread of disease to multiple organ sites, thus precluding surgical cure. Unfortunately, conventional chemotherapy also fails to eradicate most human cancers, including aggressive breast cancers, once they have spread to distant metastatic sites. Most troubling is that even early detection of some aggressive breast cancers, which appear to be small and confined to the breast parenchyma at diagnosis, does not guarantee a cure, since distant metastasis may occur early in these aggressive tumor types.

Breast cancers that lack expression of the ERBB2, estrogen and progesterone receptors, so-called "triple-negative" breast cancers (TNBC), represent the tumor type with the poorest outcome and for which no targeted agents are currently available. Poor outcome of patients with TNBC is likely due to at least two features: (1) TNBCs divide rapidly and have aggressive features and often cause early tumor metastasis. These aggressive tumors have been shown to have stem cell-like features, which likely contribute to their early dissemination to distant sires within the body and their ability to take root at these distant sites to form metastatic cancers. (2) Clear biomarkers and targeted therapies for TNBC are thus far lacking, indicating that new approaches are urgently needed against this aggressive tumor type.

Multiple clinical studies have also identified TNBC as occurring far more frequently in African-American and in Hispanic women than in white American women. Breast cancer mortality rates are also higher among African-American women, suggesting that a later stage at diagnosis, diminished access to healthcare, and the more frequent occurrence of aggressive TNBC result in worse outcome. This proposal seeks to target this health disparity by identifying novel targeted therapeutics that will have utility in the aggressive TNBC tumor sub-type.

A major advance over the past decade has been the use of gene expression analysis to both define different types of breast cancer as well as to predict clinical outcome. Our laboratory, as well as a few others, has identified a strong connection between overexpression of the MYC cancer gene with receptor TNBC in patient samples. Unfortunately, because of its function as a transcription factor, no drug-like small molecule inhibitors that directly inhibit MYC function are currently available for clinical study. Key challenges are to identify new therapeutic strategies, termed synthetic-lethal approaches, that will allow selective killing of aggressive breast cancers for which MYC is overexpressed.

This project will take a multipronged approach to identify new therapeutic targets in MYC-driven TNBC against which new treatments can be developed. The proposed studies will incorporate gene expression data from patient tumor samples, functional studies using breast epithelial cells in which the expression of the MYC gene can be regulated, as well as transgenic mouse models of breast cancer in which MYC expression can be temporally controlled. We will investigate several pathways including tumor metabolism, small RNAs and tumor stem cells to identify new therapeutic targets against TNBCs. If successful, we anticipate that the new targets for therapy identified in these basic studies will begin clinical testing within the next 3-5 years.