The transcription factor activator protein family of genes in mammary gland development and breast cancer progression

Breast cancer is currently the second most common form of cancer and the second leading cause of death due to cancer in the United States. Breast cancer itself is subdivided into at least four subtypes, luminal A, luminal B, HER2-enriched, and basal-like, based on genomewide molecular expression patterns. Luminal A is the most common form and typically characterized by high levels of estrogen receptor (ER). HER2-enriched cancers usually, but not always, harbor amplified copies of the HER2 oncogene. Luminal B cancers share characteristics with the luminal A and HER2-enriched subtypes. Finally, basal-like cancers are more oftentimes defined by their lack of any markers or molecular targets. Thus, they are often called triple-negative breast cancer. Recent evidence suggests that there are a number transcription factors that play critical roles in the cancer progression of these malignancies. Indeed, TFAP2C has been clearly shown to positively regulate ER in luminal A cancers. Alternatively, TFAP2A appears to play an interesting, but as of yet incompletely, understood role in basal-like cancer. There has been additional evidence that suggests TFAP2C regulates multiple members of the ErbB family of receptor tyrosine kinases. Thus, we hypothesize that the TFAP2 family of transcription factors play a critical role in breast cancer progression. More specifically, we will show that TFAP2A and TFAP2C not only regulate a few critical genes in luminal and basal-like cancer, but instead are responsible for the genomewide expression pattern of these two breast cancer subtypes. Moreover, we argue that TFAP2C's regulation of certain receptor tyrosine kinases in luminal A cancers indicates promising therapeutic targets, particularly with small molecule inhibitors that are already FDA-approved. In addition, we provide data suggesting that TFAP2C likely plays an oncogenic role in HER2-positive breast cancer, possibly through the regulation of certain members of the ErbB family of receptor tyrosine kinases, such as EGFR. To address these points, we use a combination of genetically engineered mouse models, xenografts, siRNA mediated knockdown technology, western blot, qPCR, and number of additional molecular biological techniques. These results will not only establish the family of TFAP2 family of proteins as critical regulators of cancer progression, but our findings will specify how and to what extent each subtype of breast cancer is affected by individual members of the TFAP2 family of transcription factors.