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Margaret Neville, Ph.D.
Ph.D.,
University of Pennsylvania Professor
and Chief of the Section of Basic Reproductive Science Joint
Appointments: Physiology
and Biophysics, Cell and Structural Biology The
major interest of my laboratory is the regulation the development of the
normal breast. 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 will be using transgenic mice with defects in this pathway 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. Recent
publications: Nguyen,
D.D., Parlow, A. and Neville, M.C. (2001)
Hormonal regulation of tight junction closure in the mouse
mammary epithelium during the transition from pregnancy to lactation.
J. Endocrinol. 170:347-356.
McManaman, J. L., Palmer ,C. , Wright, R.M.
and Neville, M.C. (2003)
Developmental regulation of XOR expression and localization in
mammary epithelial cells. J.
Physiol. In Press Neville,
M.C. (2001) Anatomy and Physiology of Lactation.
Ped.Clin. N.A. 48:13-35. Muller,
W.J. and M.C. Neville. (2001)
Introduction: Signaling in mammary development and tumorigenesis. Journal of Mammary Gland Biol. Neoplasia. 6:1-5 Neville,
M.C., McFadden,T.B., Forsyth,I. (2002) Hormonal regulation of
mammary differentiation and milk secretion.
J. Mammary Gland Biol. Neoplasia. 7: 49 – 66.
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