ddn Cancer Research News Exclusive: Making progress with progenitors

Study has identified new types of mammary gland progenitor cells that could explain the origins of breast cancer subtypes

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CAMBRIDGE, United Kingdom—It's well known that thereplication of damaged cells is the basis cancer, but some of the latestresearch from across the pond has revealed two new types of immature cells inmammary glands that might provide new answers as to what kinds of cells certainbreast cancers begin life as.
A research team at Cancer Research UK's Cambridge ResearchInstitute has published a study identifying at least two types of progenitorscells: estrogen positive progenitors, which have estrogen receptors, andestrogen negative progenitors, which do not. Progenitor cells, unlike stemcells, can only divide a certain number of times. Prior to this discovery, onlyone type of progenitor cells in mammary glands had been identified, aheterogeneous population that is associated with basal-like breast cancer.
"This exciting discovery reveals that mammary glands aremuch more complicated than scientists initially thought," Dr. John Stingl ofthe Mammary Stem Cell Biology Laboratory at Cancer Research UK's CambridgeResearch Institute said in a press release. "Uncovering new types of 'mother'cells may explain why there are different types of breast cancer, and why youngand older women tend to get different types. It could also provide new startingpoints for ways to diagnose and treat the disease in the future."
Stingl, author of the study which appears in BreastCancer Research, says his introduction tothese new cells began about 10 years ago. While analyzing normal breast tissuesamples with flow cytometry, Stingl noticed the luminal progenitor compartmentwas not uniform across all samples, with some samples presenting "not one, buttwo coherent populations" of cells. Stingl "suspected something," he says, butit has taken a number of years "to figure out how to reproducibly subdividethese populations and to characterize them."
The new progenitor cell types could be linked to known typesof breast cancer. Estrogen positive progenitor cells fare better in anenvironment with low estrogen and progesterone (such as the breast tissue ofpost-menopausal women), and luminal A and B—estrogen receptor positive tumorsthat account for 60 to 65 percent of all breast cancer—share geneticsimilarities with estrogen positive progenitor cells, according to Stingl.Estrogen negative progenitor cells present with a genetic fingerprint similarto that of basal-like breast cancer.
It's unknown whether one of the groups of progenitor cellsis more cancer-prone than the other, Stingl says.
This new information, and other recent discoveries inoncology, is changing preconceptions as to what the main culprit might be interms of cells with the potential or predisposition to become cancerous.
"The previous line of thought was that tumors originated intissue stem cells because these cells were long-lived enough to accumulate allthe genetic mutation necessary to make a normal cell malignant; however, MattSmalley published a paper in Cell Stem Cella couple of years ago demonstrating that basal-like breast cancer, at least ina mouse model of breast cancer, originates in estrogen receptor negativeluminal progenitors," explains Stingl. "This has shifted thinking of the field,and more people are now becoming convinced that breast tumors may have theirorigin in luminal progenitor cells rather than basal stem cells."
It must be pointed out, Stingl adds, that "this line ofthinking is probably too simplistic" given the complexity of cancer. He notesthat a recent Nature publication showedthat "the luminal cell compartment (a cell compartment that we thought did notcontain stem cells, but only progenitor cells and mature cells) does in factcontain a population of stem cells – so it seems that at least one (or possiblymultiple) progenitor cell types do have stem cell properties, although we don'tknow which ones."
Determining the cell of origin in cancer "is a difficultthing," Stingl says, given that cancer is the result of multiple mutations. Apresiding hypothesis is that the first several mutations might begin in a stemcell, mutations which are then passed on to more mature progenitor daughtercells, which themselves acquire more mutations and pass them on to theirdaughters, which may end up being the differentiated cells. Those cells, Stinglexplains, "then acquire the final mutation that makes them fully malignant." Sowhile
"the stem cell acquired the first genetic hit … the maturecells are the ones that propagate the tumor. Thus the cell of origin of cancergets to be a bit fuzzy." 
Moving forward, Stingl says he and his colleagues are"examining the cellular context of common breast cancer mutations," todetermine if expression of cancer-causing genes have the same effects indifferent types of breast cells, or if they tend to present specifically incertain cell types. In addition, he says the team is also "reverse-engineeringtumors on different normal cell backgrounds."
"This research takes us right to the root of how breastcells develop. This fresh understanding could reveal new ways to block thedevelopment of cancer and tell us more about what happens when tumors becomeresistant to treatment," Dr. Julie Sharp, Cancer Research UK's senior scienceinformation manager, said in a press release. "Cancer Research UK is a majorfunder of breast cancer research in the UK. Our research has contributed toprogress that means eight out of 10 women now survive breast cancer for morethan five years, compared with five out of 10 women in the 1970s. But there'smuch more to do. Research like this will build on our understanding of breastcancer to bring forward the day when we can beat this disease."

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