| Breast cancer has been reported to be the leading diagnosed and the second most fatal type of cancer among women. The initiation, progression, and metastatic cycle of breast cancer incorporate a multitude of different cell types, pathways, and genetic variability. This complexity creates a difficult barrier to overcome when generating chemotherapeutics that require targeting a pathway and/or factor that regulates as many of these numerous factors associated with breast cancer. Also, overcoming resistance and side effects associated with these chemotherapeutics could be defined as the third degree of breast cancer pathophysiology.;My specific aims are three-fold: (1) Determine if SIRT1 influences Wnt/beta-catenin signaling within breast cancer, (2) Determine the influence of SIRT1 on aromatase in breast cancer, and (3) Provide clinical statistical correlation of SIRT1 expression in human breast cancer tissue. Through these aims, I will test the hypothesis that SIRT1 is an upstream regulator of both Wnt/beta-catenin pathway signaling and aromatase expression and should be considered as a key upstream regulator in breast cancer progression and a potential chemotherapeutic target.;The results from my dissertation primes SIRT1, a Class III NAD+-dependent histone deacetylase, as a future target for chemotherapeutics that can relinquish the hold of breast cancer resistance, target a large array of oncogenic pathways, and ultimately subdue the threat of breast cancer. The Wnt/Beta-catenin pathway has been shown to be a pathway capitalized on during breast cancer progression. In its discovery, the oncogenic potential of Wnt genes was demonstrated in the early work of Nusse and Varmus where the disruption of Wnt genes by the integration of MMTV resulted in mammary tumors. In addition, studies have shown that breast cancer tissue exhibits an increase in Wnt signaling markers and a decrease in Wnt inhibitors. Also, downstream Wnt target genes include factors utilized in cell survival and proliferation. The relationship between estrogen and breast cancer risk has been extensively studied. However, clinical trials have revealed episodes of breast cancer resistance with Selective Estrogen Receptor Modulators (SERMs) and significant side effects with Aromatase Inhibitors due to aromatase ubiquitous expression. Therefore, more selective methods of anti-estrogen therapies are needed. |
