Cells lining milk ducts hold key to spread of common form of breast cancer

When a form of cancer that begins in the milk ducts of the breast invades neighboring tissue to spread to other parts of the body, the cause lies not in the tumor cells themselves but in a group of abnormal surrounding cells that cause the walls of the duct to deteriorate like a rusty pipe, according to a new study led by Dana-Farber Cancer Institute researchers.

The discovery, reported in the May 6 issue of Cancer Cell, may lead to screening tests to determine whether the disease - known as ductal carcinoma in situ, or DCIS - is likely to spread beyond the ducts, based on genetic abnormalities in cells in the ducts' lining. And it sets the stage for treatments that, by targeting these abnormalities, shore up the duct walls and keep the cancer contained.

"Women whose DCIS has invaded the ducts are known to have a greater chance of metastasis, or spreading disease. But it hasn't been clear what causes the transition from a localized cancer to invasive disease," according to the study's senior author, Kornelia Polyak, MD, PhD, of Dana-Farber. "This study demonstrates that in DCIS of the breast, and potentially in other cancers that originate in duct tissues, the answer may lie in the tumor's microenvironment - the cells and tissue that surround the cancer."

DCIS is expected to be diagnosed in nearly 53,000 women in the United States this year. When detected and surgically removed before it has a chance to spread, the disease is nearly always curable. It isn't known how many of these cancers would become invasive breast cancer if they weren't treated, but studies suggest that most of them eventually would.

Researchers initially thought that DCIS might become invasive as a result of genetic changes in the cancer cells. When they surveyed gene activity in immobile DCIS cells and in those that had spread, however, they found no significant differences. That led them to consider the cell's microenvironment.

Polyak and her colleagues focused on myoepithelial cells, which form part of the lining of the milk ducts and are involved in breast development, as well as impeding the growth and invasiveness of some cancer cells. To study what role, if any, these cells play in DCIS, the researchers worked with a specially engineered line of cells known as MCFDCIS.

When injected in laboratory animals, the MCFDCIS cells formed DCIS-like tissue that developed into invasive tumors, providing a good model of what happens in human disease. When researchers injected both MCFDCIS and myoepithelial cells into the mice, DCIS tumors arose, but they were confined to the ducts. When they injected MCFDCIS cells and fibroblasts - cells found in milk ducts and other connective tissue - the resulting DCIS tumors broke into the walls of the ducts.

"These findings made it clear that fibroblasts promote tumor growth and invasion, and normal myoepithelial cells suppress it," Polyak remarks. But when certain genes in the myoepithelial layer become under- or overactive, the layer breaks down and disappears, enabling tumor cells to escape.