Oct. 15 (UPI) — Researchers have discovered how changes in mammary glands to accommodate breastfeeding utilizes a molecular process believed to help pre-malignant breast cells survive, according to a study with mice.
During breaks in nursing, a critical switch determines whether breast cells that had been providing milk will survive or die. Researchers at Georgetown Lombardi Comprehensive Cancer Center, who published their findings Monday in the journal Cell Death Discovery, believe a strategy can provide a way to block the pathway that contributes to cancer.
“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,” Dr. Anni Warri, an adjunct professor at Georgetown University Medical Center and the University of Turku in Finland and lead author of the study, said in a Georgetown press release.
“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.”
Breastfeeding doesn’t set a mother up to develop cancer, the researchers said.
“Breastfeeding has been clearly associated with reduced breast cancer risk,” senior investigator Dr. Robert Clarke, co-director of the Breast Cancer Program at Georgetown Lombardi and Dean for Research at Georgetown University Medical Center, said. “That could be because, after breastfeeding is completed, pro-death programming takes over, which may kill abnormal cells.”
This pro-survival pathway may be one way a normal pathway can be co-opted by pre-cancerous cells, including those that could become breast cancer.
Autophagy, a common cellular housekeeping function, has been seen as key to different tumor types.
“It had not been known how this critical transition between ductal cell survival or death was regulated,” Clarke said. “Earlier studies had focused on a different pathway — apoptosis, a different form of cell death. We show that apoptosis pathway is separate from the UPR/autophagy switch, although the processes clearly work together.”
Mice were used for the study because they closely mirror human female breast physiology, Clarke said.
Researchers used two phases of breast remodeling after lactation — during nursing and weaning. The breast cells control this process in opposite ways.
During nursing, breast cells use a pro-survival strategy to maintain ductal lactation during short pauses — called “reversible” lactation. It maintains the milk producing cells to allow milk to be resynthesized once a pup suckles again.
During weaning, cells turn on a pro-death switch to return mammary tissue back to its “normal” non-lactation state through “irreversible” involution.
A buildup in milk protein in the ducts apparently triggers UPR, a natural cellular process, which recognizes that too much protein has been generated.
UPR then switches on the pro-survival function of autophagy to help maintain the viability of milk producing ductal cells. After pups start drinking again, lactation resumes and UPR/autophagy is turned down to its normal level.
But the buildup of milk proteins in ducts during weaning creates cellular stress that leads to autophagy switching into pro-death signaling.
“It is understandable that abnormal cells may develop in breast tissue, because the mammary gland undergoes many changes during a lifespan,” Warri said. “The breast ductal system resembles a tree. From puberty on, each menstrual cycle prompts the tree to grow a bit, but it always looks like a leafless tree in winter. But the tree grows leaves, as if it is summer, when a woman becomes pregnant and then starts to nurse.”
She said the cells in ducts differentiate to produce milk.
“During brief breaks in lactation, the ‘leaves’ shrink a little, but then bloom again when feedings resume,” she added. “After weaning, the tree returns to its dormant, winter state. This constant state of flux may contribute to accumulation of some abnormal cells.”
Researchers tested chloroquine, a drug commonly used to prevent and treat malaria that is being studied in two clinical trials aimed at preventing ductal carcinoma in situ from spreading.
They found that chloroquine inhibits autophagy during lactation and in turn allows apoptosis to proceed, pushing the breast to revert to its normal, non-lactating state.
Researchers noted this might be why some women in sub-Saharan African countries take chloroquine for malaria may have trouble breastfeeding.
“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,” 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.”
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