Address for correspondence: Dr. Daniel Medina, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030. Voice: 713-798-4483; fax: 713-790-0545.
dmedina{at}bcm.tmc.edu
Reproductive history is a consistent risk factor for human breast
cancer. Epidemiological studies have repeatedly demonstrated
that early age of first pregnancy is a strong protective factor
against breast cancer and provides a physiologically operative
model to achieve a practical mode of prevention. In rodents,
the effects of full-term pregnancy can be mimicked by a three-week
exposure to low doses of estrogen and progesterone. Neither
hormone alone is sufficient to induce protection. The cellular
and molecular mechanisms that underlie hormone-induced refractoriness
are largely unresolved. Our recent studies have demonstrated
that an early cellular response that is altered in hormone-treated
mammary cells is the initial proliferative burst induced by
the chemical carcinogen methylnitrosourea. The decrease in proliferation
is also accompanied by a decrease in the ability of estrogen
receptor-positive cells to proliferate. RNA expression of several
mammary cell-cycle-related genes is not altered in hormone-treated
mice; however, immunohistochemical assays demonstrate that the
protein level and nuclear compartmentalization of the p53 tumor
suppressor gene are markedly upregulated as a consequence of
hormone treatment. These results support the hypothesis that
hormone stimulation, at a critical period in mammary development,
results in cells with persistent changes in the intracellular
regulatory loops governing proliferation and response to DNA
damage. A corollary to this hypothesis is that the genes affected
by estrogen and progesterone are independent of alveolar differentiation-specific
genes. Suppressive subtractive hybridization-PCR methods have
identified several genes that are differentially expressed as
a consequence of prior estrogen and progesterone treatment.
Future experiments are aimed at determining the mechanisms of
hormone-induced upregulation of p53 protein expression as part
of the overall goal of identifying and functionally characterizing
the genes responsible for the refractory phenotype.
