Our Science – Vonderhaar Website

Barbara K. Vonderhaar, Ph.D.

Mammary Biology and Tumorigenesis Laboratory Head, Molecular and Cellular Endocrinology Section Laboratory Chief 37 Convent Drive Bldg 37 Room 1106A1 Bethesda, MD 20892-4254 Phone:   301-435-7587 Fax:   301-480-4727 E-Mail:   vonderhb@exchange.nih.gov

Biography

Dr. Vonderhaar received her Ph.D. from the University of Wisconsin-Madison. After postdoctoral training in mammary gland biology with Yale Topper at the NIH, she joined the NCI where she studies prolactin action in breast cancer. She was the first to purify a prolactin receptor from any source and the first to characterize a monoclonal antibody directed against the human prolactin receptor. She was also the first to demonstrate that human breast cancer cells synthesize and secrete significant amounts of biologically active prolactin. She serves as Chief of the Mammary Biology and Tumorigenesis Laboratory, Co-Chair of the Breast and Gynecologic Malignancies Faculty and Co-Chair of the Intramural Program for Research on Women's Health. Dr. Vonderhaar is a member of the Senior Biomedical Research Service.

Research

Prolactin Action in Mammary Gland Development and Tumorigenesis

The emphasis of our research is on understanding the mechanisms of prolactin (PRL) action in concert with estrogen (E), progesterone (P), epidermal growth factor (EGF), and insulin-like growth factors (IGF-I and IGF-II) in mammary gland development, differentiation, and tumorigenesis. Both in vivo and in vitro approaches are used to confirm physiological relevance.

Development of the Normal Gland
The mammary gland is a complex organ whose growth and development are controlled by the interaction of a wide variety of hormones and growth factors also involved in the etiology and progression of the cancerous state. Our emphasis has been on the interactions of prolactin (PRL), estrogen (E), and progesterone (P) during the peripubertal period and the lobulo-alveolar development of pregnancy as well as during tumorigenesis. We have shown that E and P are required to promote development of the primary/secondary ductal network in addition to other endocrine growth factor(s), and that P facilitates the formation of tertiary side-branches. The Hox-related homeobox containing gene, Msx2, is highly expressed during branching morphogenesis where our studies in vivo and in vitro showed that its expression is regulated by P in the presence of E. Concurrent with these morphological changes, progesterone receptor (PR) localizes at early branch points. During peripubertal morphogenesis PR distribution shifted from a homogeneous to a heterogeneous pattern. Concomitantly the PRL receptor (PRLR) undergoes a similar shift in pattern. The transcription factor, C/EBP-beta appears to regulate mammary epithelial cell fate resulting in the correct spatial pattern of gene expression required to permit steroid hormone regulated cell proliferation.We demonstrated differential transcription of the four PRLR isoforms by stromal as well as epithelial cells throughout development. The distribution of the PRLR in the epithelium, like that of the PR, progressed from a homogeneous to a heterogeneous pattern. Hence, while exogenous P or PRL alone was without effect on epithelial proliferation in ovariectomized mice, these hormones synergize to stimulate epithelial and stromal proliferation. We are studying changes in the vascular network that facilitates lactogenesis and tumorigenesis in the mammary gland. Our data support the conclusion that specific cell types within the mammary gland differentially transcribe VEGF and that it functions as an autocrine/paracrine endothelial growth factor under hormonal regulation. We have identified that PRL induces expression of VEGF in breast cells through an increase in the transcription factor Egr-1.

PRL and its Receptors in Breast Cancer
Additional studies aim to understand the role of PRL in the etiology and progression of human breast cancer. Specifically, we are examining the role of PRLR isoforms and autocrine/paracrine PRL in tumorigenesis and carcinogenic susceptibility. Comparisons between cancerous and adjacent, noninvolved tissue from the same breast of 23 patients showed that, on average, both PRL and PRLR mRNA expression was significantly higher in the cancerous tissue compared to the noninvolved tissue. The various forms of the PRLR differ in their cytoplasmic domains due to alternate splicing. Using 3' RACE we isolated five splice variants of the hPRLR, three of which encode the complete extracellular binding domain. Two of these isoforms, short form 1a (SF1a) and short form 1b (SF1b), possess unique intracellular domains encoded by splicing to exon 11 from exons 10 and 9, respectively. A third novel isoform (delta7/11) reflects alternative splicing from exon 7 to exon 11 and encodes a secreted soluble PRL-binding protein. Additional splice variants of SF1b and delta7/11 that lacked exon 4 (delta4-SF1b and delta4-delta7/11) were also identified. Functional analyses indicated that hPRLR-SF1b is a strong dominant negative to the differentiative function of the PRLR long form while hPRLR-SF1a is a weaker dominant negative. Differential abundance of SF1a, SF1b and delta7/11 expression was detected in normal breast, colon, placenta, kidney, liver, ovary and pancreas, and breast and colon tumors. Taken together, these data indicate the presence of multiple isoforms of the hPRLR that may function to modulate the endocrine and autocrine effects of PRL in normal human tissue and cancer.

Our collaborators are Mikiko Asai, Yokohama City University School of Medicine; Charles Brooks, Ohio State University; Patricia Berg, George Washington University; John Lydon Baylor College of Medicine; Sheila Prindiville and Jennifer Eng-Wong CCR, NCI; Mark Sherman,DCEG, NCI.

This page was last updated on 6/12/2008.