Remodeling the Mammary Gland

 Françoise Railhet, France

Scientists continue to uncover amazing things about human and animal anatomy, including discoveries related to lactation. The destruction of damaged or old cells is essential for the renewal of tissues throughout an individual’s life. The mammary gland experiences cyclical variations during menstrual cycles, and further important remodeling variations during pregnancy, lactation, and involution (the inactive state after weaning). A study by Akhtar et al in 2016 analyzed the role of Rac1 protein—an enzyme essential for tissue remodeling—in the mammary gland of mice and Françoise Railhet shares the findings of this study.

The authors of the study used a strain of female mice genetically modified to suppress the encoding gene for Rac1. In other words the modified mice were totally devoid of this enzyme (Rac-/Rac- chromosomes—meaning the gene for Rac1 was suppressed on both chromosomes). The modified mice were mated with wild-type (unmodified) male mice who had normal enzyme levels. Most of the first litter of pups (Rac+/Rac- chromosomes—meaning the gene for Rac1 was normal on one chromosome and suppressed on the other one) born from the genetically modified females and nursed by their mothers survived, although they were smaller in adulthood. However, from the second litter on, all pups born to and nursed by these mothers died of major malnutrition within 24 hours of birth. From the second litter on therefore, these genetically modified mice had become unable to breastfeed their young. The mammary glands of the mice were biopsied and analyzed, and the absence of Rac1 was observed. The absence of Rac1 resulted in the atrophy of the mammary glandular tissue and a very large increase in the diameter of the lactiferous ducts (milk-carrying ducts). Further studies in these mice and on cultured cells from their mammary glands confirmed that it was the absence of the Rac1 protein that was responsible for the abnormal development of the mammary gland.

The authors also looked at the impact of the absence of the Rac1 gene on milk composition. In the genetically modified mice, the level of gamma and beta-casein (milk proteins) was greatly lowered in the secreted milk after the second gestation. In the absence of the Rac1 gene, many genes responsible for the synthesis of various milk proteins and fats were inhibited. During the first gestation, the mammary gland appeared to develop properly. However, during the histological examination (microscopic examination of tissue), it was already observed that its development was impaired. The milk secreted after the first litter contained fewer lipids and proteins, but it was produced in sufficient quantities to feed the first litter properly. On the other hand, the histological examination of the mammary gland after weaning of the first litter showed the persistence of milk in the mammary gland in the genetically modified mice but not in wild-type mice. Therefore, it seems that the normal involution of the mammary gland after weaning does not occur in the absence of the Rac1 gene.

Mammary gland biopsies observed over time revealed that the mammary gland’s abnormalities were already present two days after the weaning of the first litter, with a large dilation of the lactiferous ducts still observed four weeks after weaning, and still present during the second gestation. In unmodified (wild) mice, the lactiferous ducts were moderately dilated in the first days after weaning, but the mammary gland had completely returned to its pre-gestation state four weeks after weaning. This suggests that Rac1 plays a major role in mammary involution, which is essential to allow the mammary gland to function normally during the subsequent breastfeeding. This was confirmed by more advanced exploration of mammary gland cell cultures, which found that in the absence of Rac1, the white blood cells responsible for removing dead breast cells could no longer “digest” the milk, which persisted in the mammary gland, rapidly inducing a massive increase in the diameter of the lactiferous ducts.

The remodeling of the mammary gland after weaning, which allows the reabsorption of the still secreted milk as well as the elimination of dead cells, is essential to the success of future lactations. Rac1 plays a major role in this remodeling in mice. The existence of this phenomenon in women remains to be studied.

Akhtar, N et al. Rac1 controls both the secretory function of the mammary gland and its remodeling for successive gestations. Dev Cell 2016; 38(5):522-35.

Françoise Railhet, is a former LLL Leader and a biologist. She is responsible for the “Dossiers de l’Allaitement [Breastfeeding Files],” LLL France’s publication for health professionals.