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A research team, led by investigators from the Georgetown Lombardi Cancer Research Center, explains how a natural and dramatic process – changes to breast glands to account for breastfeeding – uses a molecular process that is supposed to help survival of premalignant breast cells.
Their study on the mouse, published online in Discovery of cell death, shows that a critical switch that acts during breastfeeding breaks if breast cells that were providing milk will survive or die. The pathway of survival may be an example of a normal pathway that can be co-opted by precancerous cells, including those that could become breast cancer, according to the researchers.
If so, the findings could provide a strategy for blocking part of the pathway that contributes to cancer, according to the study's lead author, Anni Wärri, an adjunct professor at Georgetown University Medical Center and Turku University in Finland.
"The study, for the first time, identifies the molecular switch – the unfolded protein response (UPR), which activates autophagy – which controls the fate of breast milk-producing cells," she says.
The fact that autophagy, a common cell maintenance function, is used to keep cells alive or to mark them for destruction is important for cancer research because the survival function of autophagy has been considered essential in a number of different tumors. types. The researchers conducted this study because the role of autophagy in breast cancer and in the normal physiology of the mammary glands had not been resolved.
"We did not know how this critical transition between the survival or death of the ductal cells was regulated. Previous studies had focused on a different pathway – apoptosis, a different form of cell death. We show that the pathway of apoptosis is distinct from the UPR / autophagy switch, although the processes work clearly together, "says study principal investigator, Robert Clarke, DSc, co-director of the program. breast cancer in Georgetown Lombardi and Dean of Research in Georgetown. University Medical Center
The study used mice to study two phases of breast remodeling after lactation – a process called involution. "Because involution occurs in the same way in all mammals, what we find in mice is very close to the physiology of the woman's breast," he says.
Clarke adds that this study in no way suggests that breastfeeding prepares a mother to develop cancer. "Breastfeeding has been clearly associated with a reduced risk of breast cancer. This could be due to the fact that, once breastfeeding is over, pro-death programming takes over, which can kill abnormal cells. "
The two states of involution investigated by researchers occur during breastfeeding and weaning. They found that the breast cells controlled this remodeling in an opposite way.
During breastfeeding, breast cells use a survival strategy to maintain ductal lactation during short breaks from milking. This phase is called "reversible" involution because it keeps the milk producing cells to allow the milk to be resynthesized once the puppy sucks again. But when the pups are weaned from the breast, the cells switch to a pro-death switch in order to return the breast tissue to its "normal" non-lactation state by "irreversible" involution.
Before this study, researchers did not know how autophagy was involved during the involution and how it was different in the reversal or irreversible inversion phase.
The researchers discovered that a build-up of milk protein in the ducts triggers the UPR, a natural cellular process that recognizes that too much protein has been generated. The UPR then activates the pro-survival function of autophagy, which helps maintain the viability of ductal-producing milk cells. When puppies resume drinking, lactation resumes and UPR / autophagy is returned to baseline.
However, a considerable accumulation of milk proteins in the ducts – which occurs when the pups of mice are weaned from the breast – creates a deep cellular stress that leads to switching from autophagy to a pro-death signaling, accompanied by an increase in apoptosis, leading together to irreversible involution.
These are the reversible pro-survival signals that could support premalignant cells, says Wärri.
"It is understandable that abnormal cells can develop in the breast tissue because the mammary gland undergoes many changes over the course of life. The canal system of the breast looks like a tree. From puberty, each menstrual cycle encourages the tree to grow a bit, but it still looks like a leafless tree in winter, "she says.
"But the tree produces leaves, as if it was summer, when a woman gets pregnant and starts breastfeeding. The cells in the channels differentiate to produce milk. During short lactation breaks, the leaves contract a little, then grow back when the feeding resumes. After weaning, the tree returns to its dormant winter state, "says Wärri. "This state of constant flow can contribute to the accumulation of some abnormal cells."
Cancer can come into play when autophagy helps abnormal cells survive, she says.
To understand the mechanisms involved, researchers used both a gene-deficient autophagic mouse model and drug intervention studies in wild-type mice to inhibit (with chloroquine) and stimulate (with tunicamycin) the autophagy. Chloroquine is currently under study in two clinical trials to prevent the spread of ductal carcinoma in situ (DCIS). DCIS is a set of precancerous cells in the canal and most DCIS do not become invasive.
They discovered that chloroquine, a drug commonly used to prevent and treat malaria, inhibits autophagy during involution. This action allows the apoptosis to continue, causing the breast to return to its normal, non-lactating state. This finding supports clinical trials of the use of chloroquine to control DCIS in women diagnosed with DCIS, says Clarke. The results obtained with the mouse model deficient in autophagy gene were similar – the involution was improved and advanced. In contrast, stimulation of autophagy gave opposite results: milk-producing cells were maintained and delayed involution.
The researchers say their study could also have a significant impact on public health. The findings help explain why some women in sub-Saharan African countries who take chloroquine for malaria may have difficulty breastfeeding, explains Clarke. "If, as we think, chloroquine could help stop lactation sooner, we may be able to offer other short-term breastfeeding treatments as needed." In addition, the opposite strategy, the short-term use of a drug that stimulates autophagy, could help women with milk production difficulties or irregularities in nursing. "
"The link between breast remodeling and breast cancer is a huge puzzle and we have an important new piece to add to the new image," Wärri said.
Co-authors include Rong Hu, Lu Jin, MS and Alan Zwart, MS, of Georgetown Lombardi; David R. Soto-Pantoja and Katherine L. Cook, Wake Forest University; and Jie Liu and Toren Finkel, MD, of the National Institutes of Health.
The authors declare to have no personal financial interest related to the study.
This research was funded by the National Institutes of Health grants U01-CA184902, U54-CA149147424 and P30-CA51008 and a Defense Research Fellowship, BC112023.
SOURCE: Georgetown University
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