Cancer-Suppressing Gene Tied to Female Fertility

A gene long linked to suppressing the growth of cancer may also play a vital role in human reproduction, researchers report.

In experiments with mice, researchers found that females lacking the p53 gene had fewer embryos implanted in the uterus, less chance of becoming pregnant, and when they did conceive, they had fewer offspring. A lack of p53 did not affect the fertility of male mice, however.

"This is an amazing new function for a gene that everybody thought they knew what it did," said lead researcher Arnold J. Levine, a professor at the Institute for Advanced Study, in Princeton, N.J. "This is a gene that is not only watching over us so that we cannot get cancer, but it watches over our genome so that we can develop normally," he added.

The report appears in the Nov. 29 issue of Nature.

The p53 gene responds to a variety of stresses, such as radiation damage, in ways that allow it to protect cells against cancer, Levine explained. However, he added, "We found, quite by surprise, the normal function of p53 in the uterus of mice."

In order for embryos to implant in the uterus, a cytokine called LIF (leukemia inhibitory factor) is essential, and "p53 turns on the gene that makes LIF," Levine explained. "It's estrogen plus p53 making LIF that allows implantation."

In mice without the p53 gene, males are fine, but females only infrequently implant eggs and "the litter sizes go way down," Levine said. However, when these mice were given an injection of LIF, they reproduced normally.

Whether this finding has implications for humans isn't clear, Levine said. "We do know that humans require LIF in the uterus, but whether p53 has the same function in humans is something we are working on," he said.

Levine believes that p53 could play a part in human reproduction and infertility, but "there must be other factors as well," he said.

Defects in p53 are extremely rare in humans. "There are about 250 families in the United States that have defects in the p53 gene, a condition called Li-Fraumeni syndrome. This syndrome predisposes patients to cancer at an early age," Levine said.

One expert believes the finding could have clinical implications.

"Some humans show genetic variation in the amount of p53 they can produce and how well some of these variants of p53 function," said Colin Stewart, a principal investigator at the Institute of Medical Biology in Singapore and author of an accompanying editorial in the journal.

One study suggested that some women who have difficulty in getting pregnant tend to have the less efficient form of p53, Stewart noted.

"This may be why they have problems becoming pregnant, because the less efficient form of p53 does not make sufficient amounts of LIF that are necessary to get the embryo to attach to the wall of the uterus," Stewart said.

Drugs are currently being developed that would either improve the way p53 works or block the action of defective forms of p53, Stewart said.

"Some of these drugs may turn out to be useful in helping women conceive by improving the function of p53 in the uterus. Others may turn out to be possible contraceptives by blocking p53's function in the uterus," he added.

By: Steven Reinberg
SOURCES: Arnold J. Levine, Ph.D., professor, Institute for Advanced Study, Princeton, N.J.; Colin Stewart, Ph.D., principal investigator, Institute of Medical Biology, Singapore; Nov. 29, 2007, Nature.

Urban Women May Have Greater Breast Cancer Risk

Women who live in urban areas appear to have more dense breast tissue than their suburban or rural counterparts, new research suggests.

The finding is potentially important because women with more dense breasts have a higher risk of breast cancer.

The study, which compared women living and working in London to those living outside the city, found that city-dwelling women were more likely than their rural peers to have dense breasts.

"Our study suggests that the closer to urban and high population densities that a woman resides, and in particular works, the greater likelihood there is that she will have denser breasts," said study author Dr. Nicholas Perry, director of the London Breast Institute at the Princess Grace Hospital.

"For every 1 percent increase in breast density, there is said to be a 2 percent increase in the relative risk of developing breast cancer," he added.

Perry was to present the findings Monday at the Radiological Society of North America's annual meeting, in Chicago.

Each year, nearly 180,000 American women are diagnosed with invasive breast cancer, and about 40,500 die from the disease, according to the American Cancer Society (ACS). Over a lifetime, about one in eight women will develop breast cancer.

Known risk factors include a family history of the disease, getting your first period before the age of 12, beginning menopause after age 55, not having children or having your first child after 30, being overweight, drinking more than one alcoholic drink a day, and living a sedentary lifestyle, according to the ACS.

The new study included digital mammograms from 972 women, between 29 and 87 years old, living or working in rural, suburban and urban areas. Two hundred and twenty-five women were from rural areas, 135 lived in the suburbs, and 257 women either lived or worked in an urban area.

Breast density isn't an indicator of breast size, noted Dr. Julia Smith, director of the New York University Cancer Institute's Breast Cancer Screening and Prevention Program. Instead, breast density indicates more glandular breast tissue and ducts rather than fatty tissue. That means more area for breast cancer to develop and hide, she explained.

Overall, 26 percent of the women in the study had breasts that were classified as fatty, while the remaining women had density findings ranging from scattered to extremely dense. Thirty-one percent of the rural residents had breasts classified as fatty, while 26 percent of suburban women and just 22 percent of urban women did.

Perry and his colleagues found that women who lived and worked in a city were more likely to have dense breasts than either their rural or suburban counterparts. Urban women had a 54 percent greater chance of having dense breasts than women living in rural areas, and suburban women had a 14 percent higher risk of dense breasts than rural women.

"This is an interesting finding," Smith said. "But, we need to tease out the confounding factors. Are these population issues or does being in an urban environment increase risk?"

For example, she said, urban women may have better diets and may exercise more, both of which can contribute to denser breast tissue, Smith said.

Perry also said there are many lifestyle factors that need to be considered, and he hopes that now that he and his colleagues have drawn attention to the issue, more studies will be done to uncover the cause of this disparity.

One concern that Perry has is that past studies have found that urban women may be less likely to undergo screening for breast cancer, and this study suggests that it may be even more important for these women to get mammograms as recommended.

"All women should be given the opportunity to participate in breast screening programs, if eligible, but perhaps women in the city need to be extra vigilant in this regard and not miss out," Perry said.

By: Serena Gordon
SOURCES: Nicholas Perry, M.B.B.S., consultant radiologist, and director, The London Breast Institute, The Princess Grace Hospital, London; Julia Smith, M.D., Ph.D., director, New York University Cancer Institute's Breast Cancer Screening and Prevention Program, and director, the Lynne Cohen Breast Cancer Preventive Care Program, New York University Cancer Institute and Bellevue Hospital, New York City; Nov. 26, 2007, presentation, Radiological Society of North America annual meeting, Chicago.