Carcinogenesis, Vol 19, 1573-1581, Copyright © 1998 by Oxford University Press
L Sivaraman, LC Stephens, BM Markaverich, JA Clark, S Krnacik, OM Conneely, BW O'Malley and D Medina
One of the most consistent results in the epidemiology of human breast
cancer is the inverse relationship of risk and early full-term parity. The
goal of this study was to investigate the molecular mechanisms through
which early full-term pregnancy protects the breast from cancer
development. We used Wistar-Furth (WF) rats as our experimental system and
mimicked pregnancy using estrogen and progesterone (E/P). Sexually mature
female rats were treated with steroid hormones for 21 days and after 28
days of gland involution, the rats were administered MNU. Rats that
received a high dose of 20 microg E and 20 mg P exhibited an 82% reduction
in the incidence of mammary adenocarcinomas as compared to the rats
receiving only blank pellets. Decreasing doses of E/P were partially
protective suggesting that complete differentiation of the gland was not
required for refractoriness. We measured the RNA expression levels of
several target genes involved in the regulation of mammary cell
proliferation and/or differentiation including estrogen receptor (ER) and
progesterone receptor (PR), cyclins D1 and D2, the cell cycle inhibitors
p16, p21 and p27, and the tumor suppressor p53. At the time of MNU
treatment we found no significant differences in the expression of these
genes, with the possible exception of p21, indicating that hormone
treatment did not result in constitutive changes in expression levels. The
numbers of apoptotic cells were low and comparable in the hormone exposed
and age-matched virgin gland (AMV) at the time of carcinogen challenge and
remained low for 8 days after MNU treatment. The number of BrdU-labeled
cells at the time of carcinogen challenge were also low in both the AMV
(1.8%) and hormone exposed (0.8%) animals. In contrast, cell proliferation
in the AMV (5.7%) was significantly different from both the parous
involuted (1.2%) and the E/P-treated involuted (1.5%) animals 8 days after
MNU treatment. We interpret these data to indicate that hormone treatment
results in mammary epithelial cells that have persistent alterations in
intracellular pathways governing proliferation responses to carcinogens.
ARTICLES
Hormone-induced refractoriness to mammary carcinogenesis in Wistar- Furth rats
Department of Cell Biology, Baylor College of Medicine, Houston, TX 77030, USA.
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