Having children and breastfeeding reduces breast cancer risk by triggering immune system, study finds

One of the earliest clues that having children may help to protect women against breast cancer came from historical studies of nuns.

More than 300 years ago, researchers observed that women who dedicated their life to religious service — most of whom never gave birth — had "some of the highest rates of breast cancer", medical oncologist Sherene Loi said.

"This led scientists to suspect that child rearing and breastfeeding were protective, while being nulliparous [never given birth] was a risk factor," Professor Loi, a clinician scientist at the Peter MacCallum Cancer Centre, said.

Over time, evidence of this protective effect was confirmed, though the reasons behind it were not entirely clear, and thought to be largely the result of pregnancy-related hormonal shifts.

But new research, published today in Nature, provides another biological explanation, and points to the lasting impact child-bearing and breastfeeding can have on a woman's immune system.

The study, led by Professor Loi, found that women who had children and breastfed had more specialised immune cells — known as T cells — in their breast tissue, which "act like local guards, ready to attack abnormal cells that might turn into cancer".

"Pregnancy and breastfeeding leave behind long-lived protective immune cells in the breast and the body, and these cells help to reduce risk and improve defence against breast cancer, particularly triple-negative breast cancer," Professor Loi said.

In Australia, breast cancer is the second-most diagnosed cancer, and the most common cancer among women. 

Triple-negative breast cancer is an aggressive subtype that does not have any of the three receptors commonly found on breast cancer cells, and often occurs in young women.

Professor Loi said the fact women were increasingly giving birth later and breastfeeding less was likely contributing to the rising incidence of breast cancer seen in younger women.

"There are many other lifestyle factors that contribute … but it's largely believed these reproductive issues have contributed."

Breastfeeding linked to lasting immune protection

To understand how a woman's reproductive history can shape her breast immunity, the researchers first studied 260 women who either had a breast reduction or preventative mastectomy.

"What we did find is that women who had children had more of these T-cells in their healthy, cancer unaffected breast tissue," Professor Loi said.

"And when we looked at some of this tissue that was collected many, many years after their last child, these T-cells were very long-lived."

Next, the researchers sought to understand whether child-bearing and/or breastfeeding — and subsequent changes to breast immunity — had a protective effect against breast cancer.

To do this, they studied three different groups of mice: mice with pups, mice without pups, and mice that had undergone a full 28-day lactation and weaning cycle, Professor Loi said.

"When we implanted cancerous cells into their mammary fat pad, the equivalent of their breast tissue, we found these cancerous cells grew less in the mice that had undergone pups and full lactation."

In the mice that had both given birth and lactated, the tumours were smaller, and importantly, had "lots of T cells within the cancer, suggesting there was some kind of immune activation going on", Professor Loi said.

To confirm it was the T cells directly responsible for this effect, they depleted the T cells from the mice that had lactated, and found the protection was lost: "the cancers grew just as fast", Professor Loi said.

"We also observed these T cells were not only from the breast … but also recruited from circulation, suggesting that the whole process of pregnancy and breastfeeding changes your immune system, not only in the breast, but also systemically," she said.

Finally, to see whether this protective effect against breast cancer found in the lab was also evident in humans, the researchers analysed two studies of more than 1000 women diagnosed with triple-negative breast cancer.

"What we found is that women who had breastfed did better than those who had not breastfed, and their tumours actually had more immune cells … suggesting there was ongoing immune activation and regulation from the body against their breast cancer," Professor Loi said.

How much does having children and breastfeeding reduce the risk?

Research has previously shown that a woman's risk of breast cancer decreases by about 7 per cent for each child she has, while every five months of breastfeeding appears to reduce her risk by about 2 per cent.

But quantifying this protection is "nuanced", Professor Loi said, since a woman's risk of breast cancer actually increases in the short-term after childbirth, but is followed by a long-term protective effect.

Complicating matters is the fact that some women have been found to have a higher risk of triple-negative breast cancer if they have children but have not breastfed, compared to women who have never had children at all.

African American women, for example, have a higher rate of triple-negative breast cancer, which Professor Loi said appeared to be linked to women having more children, on average, and lower rates of breastfeeding.

"So [having] more children … has to be associated with more breastfeeding for that risk reduction [to occur], specifically against triple-negative breast cancer," she said.

But ultimately, Professor Loi said, having children does reduce a woman's risk of having other types of more common breast cancer.

"For example, [with] hormone receptor-positive  breast cancer, there's a clear association with pregnancy, number of pregnancies, and that specific type of breast cancer being reduced."

She added that the longer a woman breastfeeds, the lower her risk of breast cancer.

"It seems six months or more is probably optimal, but I think some is better than none at all."

New insights for prevention and treatment

Nicholas Huntington, head of the Cancer Immunotherapy Laboratory at Monash University, said the study "made a significant contribution" to scientists' understanding of how reproductive history can offer long-term protection against breast cancer.

"What this study enables us to do is get a better understanding of the immune cell types, some of the growth factors and signalling molecules that might be more important to target with emerging therapies," Professor Huntington, who was not involved in the research, said.

He noted one limitation of the study was the focus on triple-negative breast cancer, and said it wasn't clear from the mice models whether the protective effect provided by T cells would apply to other types of breast cancer.

"But there's a strong chance these types of cells are going to be beneficial to immune responses against several types of cancers, and there's data from different cancers that if you accumulate these types of immune cells, that typically you would have a better outcome."

Professor Loi also acknowledged that not all women want to, or can have, children and/or breastfeed, and that the aim of the research was to understand biology, not prescribe what any individual should do.

"Obviously breastfeeding is one option among many. Women's preferences and circumstances vary, and there are also structural issues … workplace policies, medical issues, and support," she said.

"This is more about biology and ... trying to understand the exact pathways so we can use that … to try and recreate this effect in women who don't have children or are unable to breastfeed.

In Australia, there is already one immunotherapy treatment (where the body's immune system is used to attack cancer) for triple-negative breast cancer patients. 

Professor Loi said the latest findings could be used to inform new prevention and treatment efforts.

"We know we can treat cancer with immunotherapies, but now we can move into prevention. So for breast cancer, it's not just about hormones, but about our immune system," she said.

"We can motivate breastfeeding to improve breast health … and we can develop vaccines and immune strategies to mimic this [natural] protection."