How a breastfeeding mechanism may affect breast cancer

New research shows how a normal mechanism that helps the breast adapt to breastfeeding could lead to the accumulation of premalignant breast cells.

Some of the mechanisms that enable breasts to lactate could also lead to the accumulation of abnormal breast cells.

The link between breastfeeding and breast cancer has been the subject of several studies. The National Cancer Institute quote some research which suggests that immediately after pregnancy and childbirth, a woman’s risk of developing breast cancer is higher.

However, this risk is temporary, and overall, scientists believe that breastfeeding lowers the likelihood of developing breast cancer. Only 3 percent of women with breast cancer develop the condition when they are breastfeeding.

New research helps illuminate the link between breastfeeding and breast cancer, as scientists reveal how a molecular mechanism that is a natural part of the breastfeeding process can be “hijacked” by breast cancer cells and used to help them survive.

Anni Wärri, an adjunct professor at Georgetown University Medical Center in Washington, D.C., led the new study, which was published in the journal Cell Death Discovery.

The role of autophagy in breastfeeding

Wärri and colleagues set out to study the so-called process of autophagy in mice. Autophagy is a “self-degradative process,” which fulfills important “housekeeping” roles. It helps remove dysfunctional proteins and cellular waste, among others.

The process of autophagy is largely seen as a mechanism of survival; some studies have proposed that it prevents the formation of tumors. However, the role of autophagy in both the normal physiology of mammary glands and in breast cancer has remained unclear, explains senior author Robert Clarke, the co-director of the Breast Cancer Program at Georgetown Lombardi and the dean for research at Georgetown University Medical Center.

“It had not been known how this critical transition between ductal cell survival or death was regulated. Earlier studies had focused on a different pathway — apoptosis, a different form of cell death,” says Clarke.

In the new study, the researchers show that autophagy helps control whether the cells that provided milk during breastfeeding will survive or die once the breastfeeding is over.

“The study, for the first time, identifies the molecular switch — the unfolded protein response (UPR), which activates autophagy — that controls the fate of milk-producing breast cells,” explains Wärri.

“We show that [the] apoptosis pathway is separate from the UPR/autophagy switch, although the processes clearly work together,” adds Clarke.

Reversible autophagy and breast cancer

Wärri and team examined a two-stage process of breast remodeling that occurs after breastfeeding. This process is called involution. As the researchers explain, the two stages of breast remodeling occur during breastfeeding and weaning. In the former stage, breast cells switch on their survival function in order to maintain lactation through the milk ducts when the mother takes short pauses from breastfeeding. This phase is called reversible involution.

By contrast, in the second, post-weaning stage, the breast cells turn on the “death switch.” This returns mammary glands to their normal, non-lactating state. This stage is called irreversible involution.

To study these changes, the researchers used a genetic mouse model of autophagy deficiency. The researchers also used two different drugs to either inhibit or stimulate the process of autophagy.

Wärri and colleagues found that when the mouse pups stop breastfeeding, a buildup of milk protein in the milk ducts triggers UPR. In turn, this switches on the survival mode of autophagy. When the mouse pup resumes breastfeeding and lactating begins again, UPR and autophagy dials back down to its normal levels.

However, the buildup of milk proteins that occurs during weaning triggers cellular stress which in turn, switches on the pro-death switch in autophagy.

As the lead author explains, the pro-survival signaling in reversible autophagy stage may be the one that helps pre-cancerous cells survive, as the buildup of abnormal breast cells may lead to cancer.

“It is understandable that abnormal cells may develop in breast tissue because the mammary gland undergoes many changes during a lifespan,” says Wärri. “This constant state of flux may contribute to [the] accumulation of some abnormal cells,” she adds.

Treating breast cancer with a malaria drug

Finally, the researchers also found that the malaria drug chloroquine can stop autophagy during involution, prompting the breast to go back to its normal state. These findings, explain the researchers, support the role of chloroquine as a treatment for ductal carcinoma in situ.

“These are the first preclinical in vivo data in support of a clinical trial testing an autophagy inhibitor for prevention of intraductal breast malignancy progression to invasive breast cancer,” write the authors. However, the authors clearly highlight that the findings do not mean that breastfeeding raises the risk of breast cancer.

“Breastfeeding has been clearly associated with reduced breast cancer risk. That could be because, after breastfeeding is completed, pro-death programming takes over, which may kill abnormal cells,” explains the study’s senior author.

The link between breast remodeling and breast cancer is a huge puzzle, and we have an important new piece to add to the emerging picture.”

Anni Wärri

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