February 3, 2010

New Target for Breast Cancer Therapy

Researchers identify a “cell of origin” for a common type of the disease

By Lindsay Peterson

Charlotte Kuperwasser Photo: Alonso Nichols

Researchers at Tufts have identified what appears to be the cell of origin for luminal-like breast cancer, the most common form of the disease. Their study, published in the January 19 issue of Cancer Cell, also identifies a possible target for breast cancer drugs.

Breast cancers are generally classified in one of two categories. Luminal-like cancers, which are sensitive to hormones, are the most common form of breast cancer and tend to grow more slowly. Basal-like cancers, which are not sensitive to hormones, are more aggressive and tend to have a poorer prognosis. While scientists have predicted that these cancers might arise from different types of progenitor cells, it has been difficult to identify these cells of origin.

A team of researchers led by Charlotte Kuperwasser and Philip Hinds identified different types of breast stem and progenitor cells using a novel mouse model. Progenitor cells are specialized in their functions, destined to become only one type of cell when they mature, while stem cells have the potential to develop into a variety of cell types. Previously, researchers had been unable to functionally distinguish between stem cells that make the entire mammary tissue and other progenitor cells due to the shared molecular features of these cell populations.

“Our findings show that luminal-like breast cancer originates from one type of progenitor cell—lobule progenitors—which are the self-renewing cells required to generate the milk-producing structures in breast tissue during pregnancy and lactation. Inhibiting a protein essential to these cells prevented the formation of breast tumors in mice,” says Kuperwasser, the co-senior author and associate professor of anatomy and cellular biology at the School of Medicine.

The researchers discovered that this population of progenitor cells depends on the activity of a protein called cyclin D1 for self-renewal and differentiation. In tests, mice lacking in cyclin D1 activity, compared to controls, contained very few lobule progenitor cells and had an absence of luminal-like tumors.

“The effects of eliminating cyclin D1 activity were profound,” says co-senior author Hinds, deputy director of the Tufts Medical Center Cancer Center and a professor of radiation oncology. “Depriving the lobule progenitor cells of cyclin D1 prevented self-renewal, disrupted normal mammary differentiation and blocked the formation of luminal-like tumors.”

Now that they have determined that this approach prevents mammary tumor formation, the researchers want to see “if inhibition of cyclin D1 slows or reverses the growth of existing tumors,” says Hinds. “We predict that targeting cyclin D1 would diminish the progenitor cells that drive luminal-like tumor growth.” 

“If we find that inhibition of cyclin D1 activity combats existing tumors, the protein may serve as a new target for breast cancer drugs,” says Kuperwasser, who is also a member of the cell, molecular and developmental biology genetics program faculties at the Sackler School of Graduate Biomedical Sciences.

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