One in eight American women will be diagnosed with invasive breast cancer in her lifetime, and according to the American Cancer Society an estimated 40,000 women will die from the disease this year alone. Breast cancer is a complex disease with multiple subtypes and aggressiveness, each expressing its own unique genetic profile. Over the past decade, researchers have begun to take advantage of the genetic profiles of an individual's cancers in order to determine the appropriate course of therapy. While there are some very well studied markers being used in the clinic, such as HER-2 and BRCA-1, these only represent a fraction of all cases of breast cancer. The diagnostic and therapeutic efficacy of other proto-oncogenes is vastly unexplored. This proposal aims to determine the molecular mechanisms of a putative oncogene in breast cancer, TRIM24, with the goal of using it as both a diagnostic marker and therapeutic target. Tripartite Motif protein 24 (TRIM24) is a RING-domain, E3 ubiquitin ligase, which targets p53 for proteasomal degradation, as well as a PHD/Bromodomain histone reader that recruits Estrogen Receptor (ER) and regulates specific genes in breast cancer cells. TRIM24 is over-expressed in human breast cancers, and correlates negatively with patient survival, suggesting that TRIM24 is an oncogene in breast cancer. However, a vast gap in knowledge exists regarding the role of TRIM24 in normal mammary gland development and the molecular mechanism involved in its role in breast cancer. To address this gap in knowledge I will determine the normal expression patterns and functions of TRIM24 in the mouse mammary gland during development, pregnancy and lactation; b) determine if over-expression of TRIM24 is sufficient to confer cancer-promoting phenotypes on mammary epithelial cells, and c) elucidate how specific domains of TRIM24 function in vivo. Preliminary data suggest that TRIM24 is highly expressed in the developing mammary gland and plays a role in proper development of mammary gland luminal epithelium. The experiments proposed in this application will define the function of TRIM24 in normal breast biology as well as breast cancer malignancy. This information can be value in the potential use of TRIM24 as a diagnostic marker and therapeutic target.
This proposal utilizes the well-established Mus musculus model to uncover the necessity of a multifunctional transcription factor in normal mammary gland development and tumorigenesis. While we have evidence that TRIM24 over-expression levels in breast cancer is correlated with poor patient prognosis, we do not know if this is a causative relationship. This work will illuminate the function of TRIM24 in normal breast biology as well as breast cancer malignancy which can lead to the use of TRIM24 as a predictive measure in breast cancer malignancy or redundancy, potentially leading to the development of targeted drugs.
