2006 Young Investigator Project Abstracts
The BP1 gene, mapped to 17q21.33, is a member of the distal-less (DLX) family of homeobox genes and its protein has been shown to be overexpressed in breast tumors. We hypothesize that BP1 functions as an oncogene and plays a major role in breast cancer, in particular in the progression and invasion of the disease. The objective of this project is to assess the amplification status of BP1 in breast cancer and to correlate its amplification with breast tumorigenesis. Paired samples of primary breast tumors and corresponding sentinel lymph node metastatic lesions will be evaluated using FISH analysis with both a BP1 locus specific and HER2/NEU probes (because of the close localization of HER2/NEU on 17q21). The results will be correlated with the immunohistochemistry data for both of these proteins as well as with the clinical and histopathological parameters from the patients. This correlation will be critical to understand the role of the BP1 gene in cancer progression, recurrence, and disease free survival. The long-range aim of this study is to assess the potential of using BP1 DNA amplification status as a molecular marker to predict breast cancer progression and invasion.
Prostate cancer is radioresistant to the prostate’s microenvironment that is characterized by hypoxia and low extracellular glucose concentrations. Under such conditions, stress response pathways that promote radiation resistance are activated. The AMP-activated protein kinase (AMPK) pathway is expressed in the mammalian prostate and it is activated in response to metabolic stress. Activation of the AMPK pathway in response to an increased AMP/ATP ratio leads to a therapy-resistant quiescent state involving cell cycle arrest, decreased anabolic metabolism and the increased expression of metabolic stress resistance pathways. The role the AMPK pathway plays in metabolic stress-induced radiation resistance is unclear and will be investigated. This mechanistic information is potentially important because it may provide targets for the development of radiosensitizing agents for metabolically stressed tumors.
For women who develop breast cancer, approximately 5-10% of them develop breast cancer due to having a hereditary (genetic) predisposition. For that 5-10% of women, the majority of their hereditary breast cancer is due to mutations of one of two specific genes, called BRCA1 or BRCA2. Women who carry a BRCA1 or BRCA2 mutation have a 45-80% lifetime risk for developing breast cancer. Women who know that they have a genetic mutation that puts them at higher risk for developing breast cancer can make certain medical decisions that will significantly lower their risk (for example, having surgery to remove their ovaries or breasts). Despite the benefits of genetic counseling and genetic testing, there are wide differences in its use between Caucasian and African American women. Compared to Caucasians, African Americans are far less likely to receive genetic counseling/testing. The goal of the proposed study is to identify the factors that may help explain the differences (disparities) between Caucasian and African American women’s use of BRCA1/2 counseling/testing. Specifically, we aim to identify differences between African American and Caucasian women on patient knowledge/awareness of genetic counseling and testing, physician recommendation/ referral for genetic counseling, patient access to counseling, and socioeconomic factors (e.g., ability to pay for testing and medical follow-up). We will also then evaluate actual use of genetic counseling and testing in a group of women who, based on their family history of breast cancer, are appropriate candidates for genetic counseling. Women who have recently had a breast biopsy to rule out cancer (and who do not, in fact, have cancer) will be asked to participate. In the future, we plan to develop and test new ways to increase the appropriate use of BRCA1/2 counseling and testing in underserved populations so that more women who are at risk for developing breast cancer due to a hereditary predisposition have access to and can make an informed choice about having genetic counseling and testing.
In the United States, breast cancer incidence has been increasing approximately 1% annually for the past few decades, and breast cancer remains the most common cancer in women. These data emphasize the limitations of our current approaches to breast cancer control and underline the need to focus on strategies for breast cancer prevention. Improved risk stratification for breast cancer is needed to offer appropriate options for prevention and investigation of novel chemoprevention agents. Current standards in breast cancer risk assessment were established with the introduction of the Gail and Claus models. The Gail and Claus models have significant limitations in that 70% of the women who develop breast cancer have no identifiable risk factors. Genetic assays that incorporate environmental influences on inherited susceptibility to cancer have the promise of providing greater understanding of the factors associated with breast cancer risk and improving risk stratification beyond hormonal, familial and histologic factors. Individuals differ in their inherited tendency to develop cancer. Considering the important roles of DNA repair and telomeres in maintaining the genomic integrity, it is biologically plausible that breast cancer development may be related to deficiencies in DNA repair and telomere maintenance. To address the questions regarding DNA repair and telomere maintenance in relation to breast cancer risk profiles, we propose to conduct a cross sectional study to evaluate each of these complex functions as an independent marker for breast cancer risk stratification.