Early full-term pregnancy is one of the most effective natural protections against breast cancer. Now, for the first time, an international scientific collaborative led by the Harvard Stem Cell Institute?s Kornelia Polyak, MD, PhD, has discovered why women who give birth in their early twenties are less likely to eventually develop breast cancer than women who don’t, triggering a search for a way to confer this protective state on all women.
The researchers now are in the process of testing p27, a mammary gland progenitor marker, in the tissue of thousands of women collected over a 20-year period. The medical histories of these women has been followed extremely closely to see if p27 is an accurate breast cancer predictor in a large population of women. “If the hypothesis is confirmed, likely within a few months,” Polyak, a Harvard Stem Cell Institute Principal Faculty member and Harvard Medical School professor at the Dana-Farber Cancer Institute, says, “the commercial development of a clinical test for breast cancer risk would follow.”
…If the hypothesis is confirmed, the commercial development of a clinical test for breast cancer risk [could] follow…[within a few months]…
Effect of pregnancy
In a paper just published in the journal Cell Stem Cell, the researchers describe how a full-term pregnancy in a woman?s early twenties reduces the relative number and proliferative capacity of mammary gland progenitors?cells that have the ability to divide into milk-producing cells ? making them less likely to acquire mutations that lead to cancer.
By comparing numerous breast tissue samples, the scientists found that women at high risk for breast cancer, such as those who inherit a mutated BRCA1 or BRCA2 gene, have higher-than-average numbers of mammary gland progenitors.
The researchers found significant differences in CD44+ progenitor cells where the levels of many stem cell-related genes and pathways, including the cell-cycle regulator p27, are lower in parous women without BRCA1/BRCA2 mutations. “We also noted a significant reduction in the frequency of CD44+p27+ cells in parous women. This confirms that parity-related signaling pathways play a role in regulating the number of p27+ cells and their proliferation,” Polynak noted.
In general, women who carried a child to full term had the lowest populations of mammary gland progenitors, even when compared to cancer-free women who had never been pregnant. In addition, in woman who gave birth relatively early, but later still developed breast cancer, the number of mammary gland progenitors were again observed to be higher than average.
The research suggest that pathways controlling p27+ mammary epithelial cells and the numbers of these cells relate to breast cancer risk and can be explored for cancer risk assessment and prevention.Commenting on these the results Polyak explains: ?The reason we are excited about this research is that we can use a progenitor cell census to determine who?s at particularly high risk for breast cancer. We could use this strategy to decrease cancer risk because we know what regulates the proliferation of these cells and we could deplete them from the breast.
Two important trends
Research shows that two trends are contributing to an increase in the number of breast cancer diagnoses ? a rise in obesity and the ever-increasing number of women postponing child bearing. The scientists? long-range goal is to develop a protective treatment that would mimic the protective effects of early child bearing.
Analyzing gene expression
The research, which took five years to complete, began with conversations between Polyak and John Hopkins University School of Medicine Professor Saraswati Sukumar,PhD. The two scientists formed collaborations with clinicians at cancer centers that see large numbers of high-risk women in order to obtain breast tissue samples. They also worked with genomics experts and bioinformaticians to analyze gene expression in different breast cell types.
At times, Polyak and Sukumar had trouble convincing others to help with the study, which is unique in the breast cancer field for its focus on risk prediction and prevention.
?In general people who study cancer always want to focus on treating the cancer but in reality, preventing cancer can have the biggest impact on cancer-associated morbidity and mortality,? Polyak said. ?I think the mentality has to change because breast cancer affects so many women, and even though many of them are not dying of breast cancer, there?s a significant personal and societal burden.?
For more information:
Choudhury S, Almendro V, Merino VF, Wu Z, Maruyama R, Su Y, Martins FC, et al. Molecular Profiling of Human Mammary Gland Links Breast Cancer Risk to a p27(+) Cell Population with Progenitor Characteristics. Cell Stem Cell. 2013 Jul 3;13(1):117-30. doi: 10.1016/j.stem.2013.05.004. Epub 2013 Jun 13.[Article][PubMed]
Photo: Kornelia Polyak, MD, PhD, Principal Faculty member Harvard Stem Cell Institute. Photo Courtesy: Harvard Stem Cell Institute. Illustration Credit: Sibgat Choudhury, et al., doi: 10.1016/j.stem.2013.05.004 with permission from Elsevier licenseNo: 3207270462312.
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