Department / Division
Medicine / Medicine - Oncology
Room 221A MSRB
Durham, NC 27710
Working with women with breast cancer and those at risk for developing it; providing an environment that allows patients to make empowered decisions in collaboration with a physician; supportive of alternative health care; creative approach to dealing with menopausal symptoms
Victoria Seewaldt, M.D.
Priority #1: Microenvironment in Early Mammary Carcinogenesis:
Role of extracellular matrix signaling: Interactions between normal human mammary epithelial cells (HMECs) and extracellular matrix (ECM) play a critical role in maintaining normal tissue homeostasis and are likely disrupted during the initiation of breast cancer. We developed several in vitro systems to test the hypothesis that ECM-growth regulatory and –polarity signals play a critical role in targeting the elimination of acutely “damaged” HMECs. In these models of early mammary carcinogenesis, we observed a critical role for laminin-5/31-integrin signaling in targeting the elimination of “damaged” HMECs. Funding for these studies are provided by R01 CA 88799. Recent publications include Seewaldt, et al. JCB, 2001; Dietze, et al. MRT, 2002.
Modeling the role of microenvironment in early mammary carcinogenesis: Since premalignant human breast biopsy specimens are many times required in their entirety for clinical diagnosis, it is difficult to obtain sufficient tissue for gene expression studies. For this reason, we have used our in vitro systems to focus our gene discovery efforts. In these studies we have been successful in identifying potential genes that are critical for regulating mammary epithelial cells polarity and apoptosis. With information from our in vitro data, we are currently establishing collaborations with two investigators who have heterozygote and homozygote mouse models of the genes we have identified in vitro. The strength of this approach is that we can rapidly pilot studies in human cells in vitro, confirm the phenotype in a mouse model, and then use the information to target gene expression studies in human biopsy tissue. Funding for these studies are pending R01 CA984441 (priority score 154, percentile 7.4, award letter pending). Recent publications include Seewaldt, et al. Can. Res., 2001; Dietze, et al. JBC, 2001)
Defining the role of adipose tissue in early mammary carcinogenesis: The human mammary gland is composed of ductal and luminal epithelial cells, stroma, and adipose tissue. While the role of epithelial-stromal interactions in early carcinogenesis is an area of intense investigation, the role of adipose-stromal and adipose-epithelial tissue interactions have been largely ignored. Adipose tissue represents an important local reservoir of estrogens, retinoids, prostaglandins, and perhaps carcinogens. We are currently investigating the role of retinoid receptor expression in regulating retinoid metabolism in vitro and then using these data to focus studies of adipose retinoid metabolites in early mammary carcinogenesis in human biopsy tissue. The advantage of this approach is that we can pilot studies in vitro and then rapidly translate to make optimal use of limited human specimens. Funding for these studies are provided by Susan G. Komen BCTR9834 and pending for Avon-NCI CA 68438-13 (priority score 1.8).
Investigating an extragenomic mechanism of tamoxifen signaling in p53(-) HMECs as a model of early tamoxifen chemoprevention. While the Breast Cancer Prevention Trial demonstrated a clinical benefit in the high-risk participants who took tamoxifen, many questions remain: 1) We do not understand whether true chemoprevention took place or whether the clinical benefit from tamoxifen was due to a chemotherapeutic elimination of subclinical breast cancer. 2) We also have minimal information on how tamoxifen may act in normal mammary epithelial cells that acquire mutations. p53 loss is an early event in mammary carcinogenesis. To address to this lack of information, we developed an in vitro model to test how tamoxifen may act in mammary epithelial cells that have acutely lost p53 function in the context of tamoxifen chemoprevention. We observe that while tamoxifen induces grow
This faculty member has no reported relationships with industry.