By David N. Leff
It may seem like an old wives¿ tale, but a prime risk factor for breast cancer is the age at which a woman has her first child. Recent epidemiological studies show that the younger she is when her first pregnancy comes to term, the better chance the mother has of staving off the mammary malignancy.
In the U.S. and other Western countries, the odds that a woman will contract breast cancer are one in ten. But in Asian and Latin American societies, deaths from mammary carcinoma are a small fraction of mortality compared with the disease in advanced cultures.
It figures: The statistics show that marriages in less- developed countries take place in the mid-teen years, promptly followed by pregnancy. This contrasts with wedding bells in the U.S., now usually deferred to the late 20s for brides and to the 30s for grooms.
In spite of ever-more sophisticated prevention and therapeutic strategies, such as self-palpation, mammograms, surgery and drugs, mammary carcinoma is still the second leading cause of cancer deaths in advanced nations ¿ right after lung cancer. ¿There is significant evidence that women who experience a full-term pregnancy early in their reproductive years have a significantly reduced risk for developing breast cancer,¿ observed molecular endocrinologist Bert O¿Malley, at Baylor College of Medicine in Houston.
O¿Malley, who chairs the department of molecular and cellular biology at Baylor, is senior author of a paper in the current Proceedings of the National Academy of Sciences (PNAS), dated Oct. 23, 2001, but released electronically on Oct. 15th. Its title: ¿p53 is a potential mediator of pregnancy and hormone-induced resistance to mammary carcinogenesis.¿ Its co-senior author is cell biologist Daniel Medina.
¿On the basis of our in vivo rodent findings,¿ Medina told BioWorld Today, ¿we propose the following cell-fate hypothesis¿ to explain how pregnancy hormones protect against development of breast cancer: At a critical period in adolescence, the hormonal milieu of pregnancy affects the developmental fate of a subset of mammary epithelial cells and its progeny. This results in persistent differences in molecular pathways between the epithelial cells of hormone-treated mammary glands and those of mature virgin animals.¿
Rats, Mice Affirm Cell-Fate Hypothesis¿
Human mothers are not the only mammals that succeed in warding off mammary malignancy by means of precocious pregnancy. The Baylor co-authors have reproduced this time-sensitive prophylaxis in female rats and mice, to elucidate early parity¿s hormonal mechanism.
¿We found,¿ Medina recounted, ¿that dosing the mammary glands of virgin rodents with progesterone and estrogen ¿ the master hormones of mammalian reproduction ¿ caused a rise in levels of p53, the prime tumor suppressor. When we exposed the animals to chemical carcinogens, p53 duly did its presumed duty ¿ blocking mammary gland epithelial proliferation. This outcome supported our cell-fate hypothesis.¿
In higher organisms, the p53 protein is a DNA damage-control watchdog. It acts as a rapid-response operative to counteract a variety of potential cancer-causing insults, including ultraviolet rays, ionizing radiation, chemical carcinogens and the friendly backfire of anticancer chemotherapeutic agents. To fight off these neoplastic nemeses, p53 deploys the weapons of DNA repair, cell cycle arrest and apoptosis, or programmed cell death.
Of course, when tumor growth defeats tumor suppression, mutant p53 goes over to the enemy, and promotes the increase and spread of cancers. Mutations in the p53 gene lurk in more than half of all human tumors, including over 40 percent of spontaneous breast carcinomas.
¿In our in vivo experiments,¿ Medina went on, ¿we studied 35-day-old virgin rats and five-day-timed pregnant ones. In one typical protocol, we subcutaneously implanted pellets of beeswax containing estrogen and progesterone into 48-day-old female rats. As controls, virgin animals got blank pellets. After 21 days of hormonal stimulation, we removed the pellets and allowed the mammary glands to regress for 28 days. Thereafter, on day 97 ¿ the day of carcinogen challenge ¿ we administered to both animal cohorts doses of methylnitroso urea [MNU], a strong tumorigenic compound.
¿Six to ten days following this post-carcinogen treatment,¿ he went on, ¿we focused on cell proliferative activity ¿ the ability of cells to divide ¿ and showed that the hormonal treatment blocked the carcinogen-induced proliferation. That was the early ¿ and important ¿ event. And we detected an increased frequency of estrogen-receptor-positive cells in the virgins¿ mammary glands, but not in those of the parous mother rat. The pregnancy hormones blocked the latter manifestation. And when our team repeated this rat experiment in mice, we found the outcomes in both species to be identical.¿
Medina made the point ¿that an important molecular alteration in the hormone-treated gland is the induction, sustained expression, activation and nuclear sequestration of p53 protein. This change was persistent and present at the time of MNU treatment.¿
Testing Hormone Blockage Cause And Effect
¿Right now,¿ he said, ¿our results show strong correlation between the p53 activation and the ability of hormones to induce a state resistant to carcinogens. However, we have not yet proven cause and effect, which current experiments are trying to establish.
¿We¿re also doing studies in knockout mice that have lost p53 expression,¿ Medina said. ¿We¿re treating them the same way as intact animals with p53, and seeing if the hormone-induced resistance is lost, in the absence of p53. The cell-fate hypothesis would predict that if we KO p53 we do not see hormone resistance. So what we¿re testing now is: First, do hormones activate p53? Second, can we prove the cell-fate hypothesis?¿
As for a potential clinical payoff from these insights, Medina hopes ¿that my understanding how hormones act to induce a refractory resistance state in mammary tumors proves out. Then, therapeutic effects might arise by describing the functions of those genes that have evolved, and identifying new targets to interfere with. Hypothetically, clinical applications mean answering two practical questions: How does one activate p53 without inducing pregnancy? And maybe if we identify other genes involved, how could one increase the expression of those genes, without having to get a woman pregnant?¿