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barbara
09-02-2010, 01:58 PM
Posted by Jennifer Welsh 2nd September 2010
"Scientist.com"

Some breast cancer tumors may not originate from stem cells as previously believed, according to a study published in the September 3rd issue of Cell Stem Cell. The discovery is an important step in the development of treatments for these cancers.

"Understanding the origins of these types of breast cancer is not only critical for developing preventative strategies against the disease but also for developing new targeted therapies," said Matthew Smalley, a mammary cell biologist at the Breakthrough Breast Cancer Centre in London and lead author on the study.

For years, scientists have believed that most breast cancers originated from basal stem cells, which have the ability to give rise to any of the breast tissues. But comparing mice expressing mutant versions of the BRCA1 gene, which is known to cause breast cancer, in different breast cell types, Smalley and his colleagues discovered that BRCA1 tumors actually come from progenitor cells, which can only differentiate into a single tissue type.

The BRCA1 gene, which is expressed in all cells, repairs breaks in the cell's DNA when functioning correctly. People carrying a mutated version of the gene, however, are more likely to get tumors in several tissues, including the breast and ovaries. While the BRCA1 gene doesn't cause the majority of breast cancers, carriers of the mutated gene have a much higher chance -- between 50 to 80 percent -- of getting either breast or ovarian cancer during their lifetime, and the cancers are aggressive.

Scientists used to think that these cancers came from the breast's basal stem cells because the tumors and the basal stem cells express many of the same genes. Furthermore, because such tissue-specific stem cells are long-lived and divide frequently, some have suggested them as a likely source of many types of cancer.

To determine the true origin of BRCA1 tumors, Smalley and his colleagues inserted a mutant version of the gene into either basal stem cells or luminal progenitor cells, which give rise to the cells that line the mammary gland duct. While both sets of mutation-bearing mice developed tumors, the tumors were not the same. The tumors in the mice with the mutated BRCA1 gene in their luminal progenitor cells appeared most like BRCA1 breast cancers in humans with regard to their aggressive growth and genetic markers. The tumors on the mice with the mutated BRCA1 gene in their basal stem cells, on the other hand, had characteristics of a different type of rare malignant epithelial cell cancer. It is possible that different types of breast cancers derive from different cells of origin, said Smalley.

This work builds on previous discoveries by a team lead by Jane Visvander and Geoffrey Lindeman at the Walter + Eliza Hall Institute of Medical Research, who found that there are more luminal progenitors and that they grow inappropriately in human BRCA1 tumors. "Breast luminal progenitors, rather than stem cells, should now take center stage as the likely cells of origin for the majority of basal-like breast cancers," Lindeman, who as not involved in this study, said in an email.

Smalley said he will continue to study how these and other tumors form, and what features they have in common with their origin cells, as a possible target for therapeutics. "If we can identify molecular features which these tumors have in common with the cells which we now know they originate from" he said, "we will have identified key aspects of the biology of these cancers which, when disrupted, will have therapeutic benefit."

G. Molyneux, et al., "BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells," Cell Stem Cell 7:403-17, 2010.