Margaret C. Neville Professor Cell and Developmental Biology, Physiology and Biophysics, Obstetrics and Gynecology PhD, University of Pennsylvania, 1962 UCHSC at Fitzsimons RC1-North, Room 5101 PO Box 6511, Mailstop 8309 Aurora, CO 80045 Phone: 303-724-3505 Fax: Email: Peggy.Neville@UCHSC.edu

Regulation of the development of the normal mammary gland

We are currently involved in three areas of investigation:

1. The regulation of lipid synthesis in the mammary gland. Here our focus is the mechanisms by which triglyceride is synthesized and secreted into milk. We are particularly interested in the role of the transcription factor SREBP-1 in regulating fatty acid synthesis and whether it plays a role in regulating lipid synthesis in breast cancer cells. We are using transgenic mice with defects in this pathway and dietary lipid to dissect molecular mechanisms of action.
2. Molecular mechanisms by which progesterone withdrawal activates milk secretion during the transition from pregnancy to lactation. We are currently using microarray analysis to identify candidate regulatory genes that coordinate the cellular response to progesterone withdrawal resulting in the secretion of copious quantities of milk. We have identified three candidate genes, IGFBP5, Wnt 5B and TGF-beta3 to mediate the progesterone response. We plan to use transgenic and KO mice mice to elucidate the mechanism by which these agents act.
3. Analysis of lactation defects in transgenic mice. We are currently analyzing the mechanisms by which lactation defects arise in mice overexpressing constitutively active Akt/PKB, human protein C, PKN and IGFBP5 as well as mice with a mammary specific deletion of the gene encoding HIF1". 4. Analysis of tight junction regulation in the mammary alveolar cell. We are currently defining the role of the claudins, transmembrane molecules thought to be important in cell-cell adhesion mediated at the tight junction, in the closure of tight junctions during the transition from pregnancy to lactation.

Since the pregnancy-lactation developmental cycle protects against breast cancer we believe the results of our studies are relevant both to the normal function of the mammary gland and its progression into breast cancer. Much of our work is carried out in animals, but cell culture models are also under study.

FITC-labeled dextran injected intraductally in the mammary gland of the pregnant (A) and lactating (B) mouse. During pregnancy the tight junctions (TJ) are open and dye can be seen in the space between the cells and in the intercellular space (int) including the blood vessels (bv). In the lactating gland the tight junctions are closed and the dye is confined to the lumen of the alveolus (Lu)

Selected Publications

• Monks, J. and Neville, M.C. (2004) Albumin transport across the epithelium of the lactating mouse mammary gland.  J. Physiol. . 560: 267-80..
• Blackman, B., Russell, T., Nordeen, S.K., Medina, D., Neville, M.C. (2005)  Claudin-7 expression and localization in the normal murine mammary gland and murine mammary tumors.  Breast Cancer Res.  7:R248-255.
• Rudolph, M.C.; McMamaman, J.L., Phang,T., Russell, T.A. ,Kominsky, D.J.,  Serkova, N.J., Anderson S.M., Neville, M.C. (2007)  Metabolic regulation in the lactating mouse: A milk lipid synthesizing machine.  Physiological Genomics. 28: 323-326.
• Anderson, S.M., Rudolph, M.C.,  McManaman, J.L., and Neville, M.C. (2007)  Secretory activation in the mammary gland: It’s not just about milk protein synthesis!  Breast Cancer Res. 9:on line.

Latest Publications in PubMed