The protective effect of pregnancy against breast cancer

Hormones produced during gestation induce chromatin remodeling and the reprogramming of the genes in mammary cells, according to a study conducted by scientists in Brazil and the United States.

By Karina Toledo

Agência FAPESP – Epidemiological studies indicate that women without children have a fourfold higher risk of developing breast cancer during menopause than those who become mothers while young.

An article recently published in the International Journal of Cancer by a group from the Fox Chase Cancer Center, in partnership with researchers from Universidade Estadual de Campinas (Unicamp), helps to better understand the transformations that occur in mammary cells during pregnancy that make them less susceptible to tumor development.

The study was conducted with mammary tissue samples from healthy women aged 50 to 69 who had been menstruating for at least one year. The samples were split into two groups: 42 women who never had children and were classified as nulliparous and 71 women who had given birth to one or more children and had been pregnant for the first time at an average age of 23 (with a 4.25-year variation in either direction).

Through a series of analyses, the researcher sought to evaluate if there were differences in morphology and standard gene expression in the mammary tissues of the two groups. Maria Luiza Silveira Mello and Benedicto Campos Vidal of Unicamp were responsible for evaluating the supraorganization of chromatin in the cell nucleus.

“Chromatin is the structure that contains DNA. It forms complexes with proteins (among which, are histones) and diverse types of small RNAs. When the cell enters the process of division, the chromatin compacts itself in the form of a chromosome,” explained Mello.

The analysis conducted by Unicamp researchers, funded by FAPESP, shows that in the samples from the two groups of patients, there were two different types of nuclei: one in which the chromatin was flaccid and another in which the genetic material was more condensed.

“In the samples from women who had children, the number of nuclei with more condensed chromatin was much greater. This suggests that there was an intense epigenetic modification in these cells, and it remained throughout menopause,” affirmed Mello.

The epigenetic modifications correspond to a set of biochemical processes set off by environmental stimuli that shape the functioning of the genome and, consequently, the phenotypic profile through the activation or deactivation of genes. Metaphorically, it is possible to compare the genome to computer hardware and the epigenome to the software that makes the machine work.

Among the known epigenetic mechanisms are DNA methylation – which occurs when a methylate group (formed by hydrogen and carbon particles) is added to the cytosine bases in the DNA, possibly preventing the genes from being expressed – and histone modification – which is related to the addition or subtraction of acetyl and methyl groups to the amino acids that form these proteins.

In a study conducted at the Fox Chase Cancer Center, the researchers focused their attention on two types of modifications of histones and found a much greater number of methylate protein residues in the samples from women who had children.

“In comparing the two groups, we found a difference in the expression patterns of 298 genes. There are roughly two to three times more methylated genes in the tissues from women who had children. This shows that gestation induced local reprogramming and silenced some genes that could be inadequate, such as those related to cellular proliferation,” affirmed Jose Russo of the Fox Chase Cancer Center and the main author of the study.

According to Russo, these alterations in gene expression also modify the way the cells produce certain proteins and process messenger RNA. “After pregnancy, the breast acquires a genomic signature and a different phenotypic profile. We believe that these changes give women more protection against cancer,” she said.

Early pregnancy

The results confirm the discoveries of previous research undertaken by Russo, according to which breast cells only begin to totally differentiate when they receive a stimulus from pregnancy hormones.

“We previously described four types of lobes – which are the functional structures of the breast responsible for milk production. Type 1 is the most poorly developed, much like a tree without leaves during winter. Type 4 is the most developed and is like a tree in full bloom. At the end of pregnancy, the lobes reach level 4. During this process, the mammary gland changes. The stem cells found there take on their role, and this seems to induce chromatin remodeling,” explained Russo.

However, for the pregnancy to have this protective effect, stresses the scientist, cellular differentiation must occur early, between the ages of 18 and 24. “The stem cells are more susceptible to the action of carcinogens like tobacco, alcohol and radiation than differentiated cells. The earlier the differentiation, therefore, the lower the risk of the cells favoring mutation,” explained Russo.

Aware, however, of the growing trend among women to postpone their first gestation, the researcher has focused his attention on testing a cocktail of hormones capable of mimicking the effect of pregnancy and stimulating the differentiation of breast cells.

“In rats, we have seen that this is possible and in fact protects against cancer. However, we still do not know about humans,” said Russo.