When babies stop feeding, breasts regenerate in an unusual way Image Source/plainpicture

When a woman stops breastfeeding, her breasts go from being full-time, milk-producing factories to regular appendages, in a matter of days. Now a molecular switch has been identified that controls their transformation from milk secretors to cellular eaters that gobble up their dying neighbours. The discovery could provide new insights into what goes wrong in breast cancer.

Women’s breasts comprise a network of ducts, covered by a layer of fatty tissue. During pregnancy, hormonal signals cause epithelial cells lining the ducts to proliferate and form ball-like structures called alveoli, which is where milk is made when the baby is born. However, once women stop breastfeeding, these structures self-destruct – a process that involves massive cellular suicide, and the removal of the debris.

Here is the mystery: the body’s immune cells usually remove dead and dying cells through a process called phagocytosis, yet the amount of material that is consumed is so great that you’d expect significant inflammation, pain and tissue damage – something that doesn’t typically happen when breastfeeding ceases.

“One of the least understood aspects of this process is how the excess milk and large numbers of dead cells are removed from the mammary gland without substantial activation of the immune system,” says Matthew Naylor, a cancer biologist at the University of Sydney in Australia.

After lactation, it seems that epithelial cells eat their dead neighbours. Since a protein called Rac1 is essential for normal milk production, as well as phagocytosis in immune cells, Nasreen Akhtar at the University of Sheffield and her colleagues wondered whether it might also be involved in this breast remodelling.

Breast regeneration

To investigate, Akhtar deleted the gene for Rac1 in female mice; their first litter of pups survived, but they were smaller than normal – probably because the milk they received contained less fat and protein than normal. However, subsequent litters of pubs died. Further experiments revealed that in the absence of Rac1, dead cells and milk flooded the breasts, triggering swelling and a state of chronic inflammation, which impaired the mice’s ability to regenerate their tissue and produce milk in later pregnancies.

“The mammary gland has a huge amount of stuff that it has to get rid of quickly after lactation, but if you just have immune cells taking the dead cells out, you still get chronic inflammation and tissue damage,” says Charles Streuli, who supervised the study. “Akhtar’s work shows for the first time that Rac1 is crucial for phagocytic activity, and that clearance of cell corpses and milk after lactation ceases is essential for long term tissue function.”

Besides triggering phagocytosis, Rac1 also seems to keep dying cells tethered to the alveoli for longer, possibly encouraging their neighbours to engulf them rather than leaving it to immune cells in the breast ducts. “It keeps the inflammatory phagocytes at bay, by getting the epithelial cells to do the job of clearing themselves up,” Streuli adds.

That’s not to say immune cells play no role, says Christine Watson, who also studies breast cell biology at the University of Cambridge. “In the initial phase, epithelial cells act as non-professional phagocytes to clear up milk protein and milk fat globules. However, after about three days in the mouse, macrophages (and other professional phagocytes) enter the gland and clear away the remaining cells and debris.” She adds that more work is needed to prove that inflammation occurs in the absence of this process.

The findings could have consequences for understanding the development and progression of breast cancer. Although prolonged breastfeeding reduces overall cancer risk, women have an increased risk of developing breast cancer for the first 5 to 10 years following pregnancy, and these cancers tend to be more aggressive. One theory is that inflammation during this period of remodelling after breastfeeding may fuel cancer growth.

“Given this new role for Rac1 in the removal of excess or dead cells, thereby suppressing inflammation the current study also identifies a potential role for Rac1 in breast cancer that is yet to be explored,” says Naylor.

Journal reference: Developmental Cell, DOI: 10.1016/j.devcel.2016.08.005