ORLANDO, FL—Researchers from Fox Chase Cancer Center have identified a specific genomic signature in breast tissue in parous postmenopausal women that differs from that in nulliparous postmenopausal women, according to data reported here at the American Association for Cancer Research Annual Meeting.
The researchers believe, they said, that the signature in parous women has been induced by full-term pregnancy. The molecular difference may help explain how pregnancy has a protective effect against breast cancer in women who bear children early in their lives, said Ricardo López de Cicco, PhD, Senior Research Associate at Fox Chase.
“When a woman has multiple pregnancies beginning at a relatively young age, we see a protective effect against breast cancer,” he said in an interview at the meeting. “In this study, we identified a post-pregnancy genomic signature that can still be seen even after menopause.”
Dr. Lopez said the genomic signature shows that the differentiation process is centered on up-regulation of genes related to messenger RNA splicing and that this could be the ultimate mechanism mediating the protection of the breast, conferred by full-term pregnancy.
“This is quite a change in the [current] paradigm of protection against breast cancer, because people right now are talking about the estrogen receptor. The biological process of messenger RNA splicing has never been associated with parity, so this is something pretty new.”
The nulliparous breast has mostly lobules type 1 in the breast, the most undifferentiated cells, and they cycle between lobules type 1 and lobules type 2, which are more differentiated.
With pregnancy they develop further, to lobules type 3, and with lactation the cells differentiate into lobules type 4.
“When women get into the menopausal years, and after hormones decrease, then the breast tissue reverts and involutes again into lobules type 1,” he said. “So all women, after menopausal years have lobules type 1, independent of whether they were parous or nulliparous.”
Dr. Lopez stressed that his point is that breast tissue in parous women has gone through the whole process of differentiation, while tissue in nulliparous women has not.
“And if the breast cannot go through the whole process of differentiation, the cell remains pretty much undifferentiated, and the likelihood of developing breast cancer is enhanced,” he said.
The breast core biopsies analyzed in this study were from healthy women, age 50 to 59, with no histological evidence of breast cancer and no previous cancer history.
By comparing gene expression in specimens from 44 postmenopausal women who had children and 21 postmenopausal women who did not, the researchers identified 208 genes that are differentially expressed. The signature was subsequently validated in an independent cohort of 61 postmenopausal women, 38 who had children and 23 who did not.
Dr. Lopez said he believes that these 208 genes, in 305 transcripts, represent the genomic signature of the effects of pregnancy, and some day may be the basis for an assay that can measure the efficacy of preventive strategies for breast cancer.
In another finding, the researchers also saw reduced expression of cancer-associated genes in breast tissue in parous women, such as a lower expression of insulin-like growth factor receptor level, compared with nulliparous women.
Also, genes involved in stem cell maintenance were downregulated in parous women, possibly because mammary stem cells have already undergone proliferation and differentiation.
This is in contrast to nulliparous women in whom stem cells are still poised to grow, Dr. Lopez said.
The research was a collaborative effort of Fox Chase, Umeå University in Sweden, and New York University, with funding from the Avon Foundation.
The senior author of the paper was Jose Russo, MD, Professor in Fox Chase Breast Cancer Research Laboratory.
So What? Opens Potential to Targeted Chemoprevention
Asked to comment on the study for this article, Robert Clarke, PhD, DSc, Professor of Oncology and Dean for Research at Georgetown University Lombardi Cancer Center, said that although the study is still early and at a very early stage, it does ask an important question and the findings hint that it is worth carrying the research forward.
It has been known for a long time that having a pregnancy early in life provides some protection from breast cancer. “What [the Fox Chase researchers] are saying is that you can see the molecular differences in later life, that these are clearly differences that persist into menopause,” Dr. Clarke said.
Still, the study begs the question of what to do with the information, “assuming it's correct,” he said.
“Just saying that parous women are different [in breast cancer risk]—we know that. But why they are different, that would be important.”
If scientists had that knowledge, he said, chemoprevention with a drug such as tamoxifen could be tailored for one population versus another.
He noted that in general, women in Western society today tend to have children at a later age. “One day we might be able to target a preventive therapy that would reduce their risk, a treatment to make their molecular profiles look like that of a woman who had children early.”
The simplest reason for a protective effect in early pregnancy, and the one that seems most likely and is most widely accepted, he explained, is that when a women goes to full term and breastfeeds, the breast tissue goes through a round of proliferation so it can gear up and make milk. The differentiation of the breast cells to make milk is thought to reduce the number of normal stem cells and therefore reduce the number of targets for malignant transformation.
At the end of breastfeeding, those cells die out and the breast goes back to a resting state, he said.
In contrast, when a woman has her first pregnancy at an older age, the breast has been through multiple menstrual cycles, and there may be some preexisting but dormant breast cancer cells, he explained. The hypothesis is that when these women then go through pregnancy with its stimulus to proliferate, those cells start to make more copies of themselves.