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More evidence linked to normal changes, revealing invasive breast cancer



A research team led by researchers at the Comprehensive Cancer Center Georgetown Lombardi describes how a natural and dramatic process – changes in the mammary glands to allow breastfeeding – uses a molecular process that contributes to the survival of premalignant breast cells ,

Their mouse study, published online in Cell Death Discovery shows that a critical switch that works during breastfeeding controls whether breast cells that have delivered milk will survive or die. The pro-survival pathway could be an example of a normal pathway that can be co-opted by precancerous cells, including those that could become breast cancer, the researchers said.

If this is the case, the results could be a strategy to block a part of the pathway that contributes to cancer, says the lead author of the study, Anni Wärri, an associate professor at Georgetown University Medical Center and the University of Turku in Finland.

"The study identifies, for the first time, the molecular switch ̵

1; the unfolded protein response (UPR), which activates autophagy – that controls the fate of breast milk-producing cells," she says.

The fact that autophagy, a common cellular household function, either serves to keep the cells alive or to mark them for destruction, is important in cancer research because the pro-survival function of autophagy is key in a number of different types of tumors was seen. The researchers performed this study because the role of autophagy in both breast cancer and normal mammary gland physiology was unexplained.

"It was not known how this critical transition between dual-cell survival or death was regulated." Previous studies had focused on a different pathway – apoptosis, another form of cell death. "We show that the apoptosis The pathway is disconnected from the UPR / autophagy switch, although the processes clearly work together, "says Robert Clarke, DSc, co-director of the Breast Cancer Program at Georgetown Lombardi and Dean for research at Georgetown University Medical Center

The study used mice, to study two stages of breast modeling after lactation – a process known as involution. "Because involution occurs in the same way in all mammals, what is found in mice very much reflects female female breast physiology," says Clarke.

Clarke adds that this study by no means indicates that breastfeeding is the mother of cancer. "Breastfeeding is clearly associated with a reduced risk of breast cancer, which may be due to the fact that after breastfeeding, pro-death programming is adopted, which can kill abnormal cells."

The two stages of involvement studied by the researchers occur during breastfeeding and breastfeeding Weaning up. They found that breast cells control this remodeling in an opposite way.

During breast-feeding, breast cells use a pro-survival strategy to maintain milk production during short milking breaks. This phase is called "reversible" involution because it keeps the milk-producing cells so that the milk can be resynthesized as soon as a baby sucks again. But when pups are weaned off the chest, the cells turn to a pro-death switch to return the breast tissue to its "normal" non-lactation state by "irreversible" regression.

Prior to this study, the investigators did not know how autophagy works during involution and how it differs in the reversible from the irreversible phase of involution.

Researchers found that a buildup of milk protein in the channels triggers UPR, a natural cellular process that recognizes that too much protein is present. The UPR then turns on the pro-survival function of autophagy, which helps maintain the viability of milk-producing duct cells. When the puppies start drinking again, lactation resumes and UPR / autophagy is lowered to baseline levels.

A considerable accumulation of milk proteins in the ducts, which occurs when mouse cubs are deposed from the chest, produces a strong cellular stress leading to autophagy, which transitions into pro-death signaling, accompanied by an increase in apoptosis together leads to an irreversible involution.

It is the reversible stage of pro-survival signals that premalignant cells can receive, says Wärri.

understands that abnormal cells can arise in breast tissue because the mammary gland undergoes many changes over its lifetime. The chest duct system is similar to a tree. From puberty, every menstrual cycle requires the tree to grow a bit, but in winter it always looks like a bare tree, "she says.

" But the tree grows leaves as if it were summer, when a woman becomes pregnant and then begins to breastfeed. The cells in the channels differ to produce milk. During the short lactation pauses, the leaves shrink a little, but then reappear when the feeding resumes. After weaning, the tree returns to its dormant winter state, "says Wärri." This constant flow state 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, the researchers both used an autophagy gene-deficient mouse model and drug intervention study in wild-type mice that both inhibit (with chloroquine) and stimulate autophagy (with tunicamycin) Chloroquine is currently a drug is being studied in two clinical trials to prevent ductal carcinoma from spreading in situ (DCIS) DCIS is a collection of precancerous cells in progress and most DCISs are not becoming invasive.

They found that chloroquine, a drug commonly used to prevent and treat malaria that inhibits autophagy during involution ction allows apoptosis to continue with the breast returning to its normal, non-lactating state. This finding provides support for the clinical trials that tested the use of chloroquine to keep DCIS at bay in women diagnosed with DCIS, Clarke says. The results with the autophagy gene-deficient mouse model were similar – involution was enhanced and improved. In contrast, the stimulation of autophagy gave opposite results: milk-producing cells were held and the involution was delayed.

The researchers say their study could also have an important impact on public health. The results explain why some women in sub-Saharan Africa who take chloroquine for malaria have breastfeeding problems, explains Clarke. "If, as we believe, chloroquine could bring lactation to an early end, we might be able to offer alternative short-term therapies that would allow breast-feeding as needed, and the reverse strategy, a short-term use of an autophagy-stimulating drug, could be troubling for women help with milk production or breastfeeding irregularities. "

" The relationship between breast reshaping and breast cancer is a huge mystery, and we have an important new piece to add to the resulting image, "says Wärri.

Co-authors are Rong Hu, Lu Jin, MS, and Alan Zwart, MS, of Georgetown Lombardi; David R. Soto-Pantoja and Katherine L. Cook of Wake Forest University; and Jodie Liu, and Toren Finkel, MD, of the National Health Institutes.

The authors report having no personal financial interests related to the study.

This research was supported by the National Institutes of Health Scholarships U01-CA184902, U54-CA149147424 and P30-CA51008, and a postdoctoral fellowship from the BC112023

Source: Georgetown University


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