| Breast cancer remains a deadly disease representing 15% of overall cancer deaths despite advancements in diagnostics and therapeutics. In the United States, breast cancer afflicts one out of every eight women and of these one out of thirty-three die from it. The stratification of breast cancer into clinical and tumor specific features is critical to implementing adjuvant treatment. However, the etiology of cancer progression from premalignant lesions to advanced disease remains poorly resolved. Understanding the molecular mechanisms for the progression of breast cancer will lead to the development of better preventative and therapeutic strategies. Mounting evidence supports the view that genetic mutations alone are insufficient for cancer development and progression, and there are biochemical and environmental factors that are involved.; HMG-Box containing Protein 1 (HBP1) is a transcriptional repressor that inhibits muscle differentiation, regulates proliferation and induces cell cycle arrest. Wnt and EGFR signals, both of which are dysregulated in breast cancer, can be determined by HBP1. For the canonical WNT pathway target oncogenes, such as cyclin D1, c-Myc, and Cox2, HBP1 acts by competing for the binding of beta-catenin with the TCF family. Through a direct DNA binding mechanism, HBP1 represses the transcription of p47phox gene, a regulatory subunit of the NADPH oxidase. EGFR can introduce its signals to a cell through NADPH oxidase. HBP1 repression of p47 phox contributes to its ability to elicit cell cycle arrest by inhibiting superoxide production.; Previously, variant forms of HBP1 were discovered in association with invasive breast cancers. Chapter 1 shows that all seven forms of HBP1 are functionally defective. The transcriptional repression domain or the DNA binding domain is lost, rendering it unable to repress TCF binding activity to DNA or to suppress tumor cell proliferation. In support of these observations, siRNA mediated HBP1 silencing is associated with increased breast tumorigenic proliferation and invasiveness. Therefore, loss of HBP1 function may contribute to invasiveness of the disease.; In chapter 2, we investigated new strategies for suppressing invasive breast cancers. In a limited phytonutrient screen, (-)-epigallocatechin-3-gallate (EGCG), the major polyphenol in green tea, emerges as an intriguing candidate. Epidemiological studies have associated green tea consumption with reduced recurrence of invasive and other breast cancers. EGCG can block Wnt signaling by stabilizing HBP1 transcripts. In conjunction with regulation of Wnt targets, EGCG-mediated regulation of HBP1 inhibits invasive properties.; In chapter 3, we demonstrated cumulative inhibition of HBP1 and EGCG in tumor transition. Cellular senescence is a tumor suppressive mechanism of premalignant stages. (Abstract shortened by UMI.)... |
