Breastfeeding has long been shown to reduce the risk of breast cancer. Now new research is shedding light on how normal changes that breasts go through during breastfeeding could open up a pathway for some precancerous cells to survive — at least until baby is weaned.
Researchers at Georgetown Lombardi Comprehensive Cancer Center published their study “Autophagy and Unfolded Protein Response (UPR)…” in the journal Cell Death Discovery. This new research “in no way” shows that breastfeeding increases breast cancer risk, the study’s authors urge. Rather, identifying how this cancer-producing pathway functions is broadening our understanding of how normal breast changes affect cancer risk, and also leading to potential treatments.
It all comes down to a switch that decides whether milk-producing cells will live (a pro-survival pathway) or die (a pro-death pathway).
Normal Breast Changes
Breasts undergo impressive changes during pregnancy, creating more tissue so that large amounts of milk can eventually be produced to feed baby. Then, post-pregnancy, breasts undergo constant cycles of change via two different phases of involution: breastfeeding and weaning.
Involution is a normal process that occurs when an organ shrinks due to inactivity or old age. In this case, it’s inactivity. When breastfeeding, these periods of inactivity are brief, typically only a couple hours, give or take. When weaning, the breaks gradually become longer until nursing stops altogether. During these periods of involution, the cells in the mammary tissue cycle through proliferation (rapid reproduction), differentiation (when a cell changes into a different type, usually a more specialized one), cell death, and tissue remodeling.
Tissue remodeling is where the study’s newly discovered precancerous pathway lies.
“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,” says Anni Wärri, PhD, the Georgetown study’s lead author.
How Weaning Helps Cancer Risk
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A groundbreaking study released in 2016 revealed how milk-producing cells are killed after lactation ends. Originally, scientists thought the dead or now-useless milk-producing cells were removed by immune cells through a process called phagocytosis during weaning. However, that didn’t seem to be the case, since phagocytosis would likely cause massive inflammation, tissue damage, and pain — because of the amount of immune cells needed — and that wasn’t happening.
So Nasreen Akhtar, the lead scientist on the 2016 study, looked into what else could be happening. What allows the milk-producing cells to be destroyed is a molecular switch that relies on a protein (called Rac1) that is integral to milk production and tissue remodeling. In essence, milk-producing cells are cannibalized by other cells.
“We thought something else must be standing in for the immune cells,” stated Akhtar. “What we didn’t expect to find was a molecular switch that turned milk-secreting cells into cannibalistic cell eaters. We discovered that these cells were now able to eat or otherwise remove vast quantities of redundant milk-producing cells.”
Now, in the Georgetown study, researchers are finding that autophagy, the “cannibalism” of cells, is due to cellular stress. The stress flips on the “pro-death” pathway, which is irreversible. This shuts down the milk-making cells so that the breast tissue can be remodeled and return to its pre-pregnancy state.
The important thing is, while it kills milk-making cells, it may also kill any abnormal, cancerous cells that have developed.
How Nursing Affects Cancer Risk
The involution phase that occurs during nursing is considered reversible. The short pauses mom takes from nursing throughout her day don’t stop milk production altogether; rather, the production is maintained, and this allows milk to be re-synthesized when baby is put to the breast again. This strategy in involution is considered “pro-survival.”
A build-up of milk protein in the milk ducts switches on UPR (unfolding protein response), which is a natural cellular process that activates when too much protein has been produced. Then, the UPR triggers autophagy, which destroys or disables dysfunctional or useless cells, and helps right the balance of milk-producing cells.
When baby resumes nursing, lactation starts again and the UPR and autophagy go back down.
The constant cycling of cell changes may cause abnormal cells to develop in the breast. So when the pro-survival switch for autophagy is flipped and it’s determining which milk-producing cells live or die, it may allow some abnormal or cancerous milk-producing cells to survive.
The mammary involution that occurs during breastfeeding is thought to contribute to breast cancer that’s associated with pregnancy, as well as contributing to a higher likelihood of cancer cells being able to metastasize. However, manipulating the pro-survival switch could allow scientists to find a way to shut down the “pathway,” and effectively reduce any cancer risk it incurs.
Researchers tested two different types of drugs on wild mice to test their theory on autophagy during breastfeeding: a drug called chloroquine that inhibits autophagy, and a drug called tunicamycin that can stimulate it. Chloroquine is actually currently in two clinical trials about preventing the spread of DCIS (ductal carcinoma in situ, or precancer). DCIS typically doesn’t become invasive.
The study found that chloroquine does stop autophagy during lactation, so cell death can occur. This in turn makes the breast return to a non-lactating state.
“If, as we believe, chloroquine could bring lactation to an early end, we may be able to provide alternative short-term therapies that would allow breastfeeding when needed,” senior investigator Dr. Robert Clarke said. “Also, the opposite strategy, a short term use of autophagy stimulating drug, could help women with difficulties in milk production or irregularities in nursing.”Whizzco