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 growth arrest in p53(+) HMECs, tamoxifen induces apoptosis in HMECs that have acutely lost p53 function. The induction of apoptosis is independent of estrogen receptor expression and appears to utilize a calcium-mediated signal transduction pathway that exhibits cross-talk with ECM-signaling. Funding for these studies are pending R01 CA984441 (priority score 7.4, award letter pending). Recent publications include Seewaldt, et al. Canc. Res., 2001; Dietze, et al. JBC, 2001)
Priority #2: Clinical Breast Cancer Chemoprevention and Biomarker Development
Translational Breast Cancer Prevention Clinic: In order to directly translate observations made in the laboratory, we developed the Breast Wellness Clinic at Duke University. This clinic combines three existing high risk prevention efforts: 1) Hereditary Breast Cancer Clinic, 2) STAR recruitment, and 3) High Risk Breast Clinic. Risk reduction strategies encompass a wide range of approaches that include: pharmacological agents, nutritional modification, and complementary “whole person” strategies. Participating faculty span multiple disciplines including genetics, immune modulation, basic mammary biology, nutrition, complementary and alternative medicine, and medicinal chemistry. Our goal is to use the clinic to generate multi-disciplinary research collaborations to 1) investigate genetic modifiers of breast cancer risk and 2) develop interventions ranging from pharmacologic agents to stress reduction. Currently this clinic directly intersects with several major research initiatives including the Breast SPORE and the Cancer Genetics Network (CGN). The clinic also meets an essential SPORE requirement that one project focus on chemoprevention or epidemiology (Breast SPORE Project 3). Funding is for the clinic has been obtained from the V-Foundation and the Duke University Cancer Center and is pending for Avon-NCI CA 68438-13.
Biomarker Development: There are currently few prevention options for women at high risk for breast cancer. Recent studies suggest that breast cancer incidence may be substantially reduced in high-risk women by tamoxifen treatment and/or prophylactic mastectomy or oophorectomy. Although these reports are encouraging, prophylactic surgery is a drastic prevention alternative, and tamoxifen is expensive and can be associated with significant side effects. Biomarkers are needed to accurately predict short-term breast cancer risk, so that 1) women who are most likely to benefit from preventive therapy can be identified, and 2) response to chemoprevention can be accurately assessed.
In order to facilitate biomarker development, we are collaborating with Dr. Carol Fabian at University Kansas. To this aim, we are a participating site in Dr. Fabian’s Phase I/II Chemoprevention Master Agreement. Through Dr. Fabian, we have learned to perform periareolar random breast fine-needle aspiration (rFNA). rFNA is a recently-validated technique for repeatedly sampling mammary cells from the whole breast to assess both 1) breast cancer risk and 2) response to chemoprevention in high-risk women. Breast rFNA is analogous to a cervical Pap smear in its ability to identify pre-cancerous changes in a representative sampling of cells from the entire breast. Two of the great strengths of rFNA are 1) the ability to repeatedly sample field effects in the whole breast and 2) the willingness of high-risk women to undergo subsequent rFNA. Approximately 80% of women who undergo initial rFNA, undergo subsequent rFNA. The presence of cellular atypia in breast rFNA obtained in high-risk women is associated with a 4-fold increase in the likelihood of developing breast cancer. rFNA has the advantage of being able to provide a “snap-shot” of the whole breast, and unlike other techniques for sampling breast cells such as ductal lavage, rFNA 1) can be performed successfully in a majority of high-risk women (66-72% cell yield rFNA vs. 20-40% ductal lavage) and 2) has been validated in long-term chemoprevention cohorts.
Breast tissue is heterogeneous and therefore, it is expected that the breast rFNA samples we obtain in high-risk women will be similarly heterogeneous. Since high-risk asymptomatic patients, by definition, do not have a focal mass to evaluate, our goal will be to assess “field effects” in the entire breast. rFNA is an ideal technique to employ for this purpose because it was specifically designed to obtain multiple cellular samples from throughout the entire breast in high risk women. The success of this strategy, however, will depend on coupling rFNA to a risk marker whose presence alone (and not relative levels or frequency of expression) has positive predictive value for the subsequent development of breast cancer.
The absolute (and not relative) presence of cytologic atypia in rFNA is an independent risk factor for breast cancer that has been validated prospectively in a large-scale prevention cohort. Based on in vitro data, we are currently refining the sensitivity of rFNA by testing for a second potential marker for breast cancer risk, the presence of RAR2 P2 promoter methylation. Methylation of RAR2 P2 promoter appears to be a very early event in mammary carcinogenesis and methylation specific-PCR is an extremely sensitive technique. In preliminary data, we have been able to detect the presence of as few as 10 breast cancer cells with known RAR2 P2 methylation by this method. The validation of a highly sensitive marker for breast cancer risk will further enhance the utility of rFNA
We also have adapted rFNA to obtain both mammary adipose tissue and epithelial for analysis. This will permit the evaluation of mammary epithelial cytology and specific biomarker expression in the context of local retinoid, estrogen, and prostaglandin levels. We feel that this adaptation will be very important in evaluating potential epithelial cell-adipose tissue interactions to further investigate the role of microenvironment in mammary carcinogenesis.
Education and Training
- University of California at Davis, M.D. 1989
- University of Washington, Ob Gyn Intern, Obstetrics And Gynecology
- University of Washington, Medical Resident, Medicine
- University of Washington, Senior Fellow In Medical Oncology, Medicine
Selected Grants and Awards
- Combined breast MRI/biomarker strategies to identify aggressive biology
- Targeted Chemoprevention of Breast Cancer: From the Bench to Clinical Testing
- Tension-Stat3-miR-mediated metastasis
- KCNK9 Imprinting in Breast Cancer Progression and Metastasis
- The Role of HER2 Signaling Networks in Early Stage Breast Cancer Initiation and Resistance to Tamoxifen Prevention
- Connected care: Navigating underserved women to resourced screening
- Molecular Markers of Breast Cancer Risk and Prevention.
- ECM-Mediated Apoptosis in p53 (-) HMECs
- p53 loss in HMECs: A model of Breast Cancer Prevention
- Markers of short term breast cancer risk in FNA
- Brk interaction with ErbB receptors alters cell fate
- ECM-Mediated Apoptosis in p53(-) HMECs
- RAR-Beta Mediated Apoptosis in Breast Cancer Cells