Sex Steroid Hormones and Growth Factors
in Mammalian Development and Reproduction
My laboratory has four major separate, but inter-related
areas of research. These are focussed on the interactions
between sex steroid hormones, oncogenes and growth factors
in normal reproductive processes and in cancer.
(1) Regulation of cell proliferation by female sex steroid
hormones.
In the uterus, estradiol 17( (E2) stimulates a synchronized
wave of cell proliferation in the epithelium. Progesterone
(P4) completely inhibits this E2-induced cell proliferation.
We have shown that E2 stimulates cyclin D1/cdk4 translocation
to the nucleus and the activity of cyclin E and A/cdk2.
P4 completely prevents the cyclin D translocation and the
activation of cdk2. Studies are underway to determine the
mechanism of the retention of cyclin D1 in the cytoplasm
since this constitutes a unique method of cell cycle regulation
(1). This includes the identification of interacting proteins
by 2-hybrid screens and the cloning of novel cell cycle
inhibitors. In addition, we are developing novel methods
to inhibit gene expression in these epithelial cells in
vivo.
Tamoxifen, a prototype anti-estrogen, has recently been
approved for therapy for breast cancer. However, in the
uterus and bone, it is an agonist (2). In the uterus, unfortunately,
this pre-disposes women to uterine cancer. Another project,
in the laboratory, is to understand the molecular basis
of this differential response, in order to better develop
drugs that can interfere with estrogen action in one tissue
while promoting it in another tissue. Such drugs are aimed
at maintaining the beneficial effects of estrogen for diseases
like osteoporosis while allowing the inhibition of cancer-promoting
effects.
(2) Role of growth factors, particularly CSF-1, in reproduction.
Sex steroid hormones exert many of their actions through
the intermediary of peptide growth factors. Of these, we
have extensively studied the mononuclear phagocyte growth
factor, colony stimulating factor-1 (CSF-1), whose uterine
synthesis is regulated by E2 and P4. Studies on this growth
factor were dramatically enhanced by the identification
of the natural recessive mutation, Csfmop, as being a null
mutation in the CSF-1 gene (3). Using this mouse, we have
demonstrated that CSF-1 plays an essential role in the establishment
of a functional hypothalamic pituitary-gonadal axis through
its action on the brain macrophages (microglia) (4). It
also stimulates ovulation by directly affecting receptor
signalling in the oocyte and regulating placental immunity
by its action on receptor-bearing trophoblasts. We are studying
each of these processes, mostly using sophisticated transgenic
mouse technology, to activate or inhibit CSF-1 intracellular
signalling in specific cell types at particular developmental
stages.
(3) Mammary gland development and cancer.
The third project involves the role of stromal and epithelial
elements in mammary gland development and cancer (5). We
have identified macrophages as important regulators of ductal
development in the mammary gland and also for the progression
of cancer in this tissue. Studies are underway to determine
the mechanism of the trophic action of these macrophages
on epithelial growth and on angiogenesis. We have also shown
that TGF(3 regulates cells death (apoptosis) during the
first phase of involution. We are using transgenic methods
to explore the signal transduction pathways involved in
this action.
(4) Mismatch repair proteins in meiosis.
The fourth project is on gametogenesis. We have shown that
members of the mismatch repair family of proteins are essential
for meiosis in both males and females (6). In females, the
failure of meiosis during zygotene results in complete oocyte
loss and dysgenesis of the ovary. This implies that the
oocyte sends inductive signals to the ovary that maintain
its developmental progression. We are identifying novel
proteins involved in meiotic progression as well as, analyzing
the developmental consequences of oocyte loss.
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Selected References: 
1) Tong, W. and Pollard, J.W. (1999) Progesterone inhibits
estrogen-induced cyclin D1 and cdk4 nuclear translocation,
cyclin E, A-cdk2 kinase activity and cell proliferation
in uterine epithelial cells in vivo. Mol. Cell. Biol. 19:2251-2264.
2) Pollard, J.W. (1999) Modifiers of Estrogen Actions.
Science & Medicine 6:38-47.
3) Pollard, J.W. and Stanley, E.R. (1996) Pleiotropic roles
for CSF-1 in development defined by the mouse mutation,
osteopetrotic. Ad. Develop. Biochem. 4:153-193
4) Cohen, P.E., Hardy, M. and Pollard, J.W. (1997) CSF-1
plays a major role in the development of reproductive function
in male mice. Mol. Endocr. 11:1636-1650.
5) Pollard, J.W. and Hennighausen, L. (1994) Colony stimulating
factor-1 is required for mammary gland development during
pregnancy. Proc. Natl. Acad. Sci. USA 91:9312-9316.
6) Edelmann, W., Cohen, P.E., Burkhard, K., Winand, N.,
Heyer, J., Kolodner, R., Pollard, J.W. and Kucherlapati,
R. (1999) Mammalian MutS Homolog 5 is required for chromosome
pairing in meiosis. Nature Genetics 21:123-127. |
