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New Clues to Why Older Women Are More Vulnerable to Breast Cancer

Protective cells become less responsive to their microenvironment

Scientists at the Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) have gained more insights into why older women are more susceptible to breast cancer. They found that as women age, the cells responsible for maintaining healthy breast tissue stop responding to their immediate surroundings, including mechanical cues that should prompt them to suppress nearby tumors.

The investigators’ work sheds light on how aging alters cellular and molecular functions, and on how these changes contribute to the prevalence of breast cancer in older women. The disease is most often diagnosed in women 55 to 64 years of age, according to the National Cancer Institute.

The new research was published online June 5 in Cell Reports.

The scientists studied multipotent progenitors (MPs), a type of adult stem cell that is believed to be the origin of many breast cancers. Two years ago, the group found that as women age, MPs accumulate in breast epithelial tissue. They didn’t know why these cells increase in numbers, but they believed their cellular microenvironment (the matrix of tissue surrounding them) played a role.

To explore this idea, the scientists examined samples of human mammary epithelial cells from pre- and post-menopausal women. They wanted to learn how the MPs in these tissue samples were affected by changes to their microenvironments. The researchers placed the tissue on soft polymer surfaces that mimic healthy breast tissue, as well as on progressively stiffer polymer surfaces that mimic the rigidity of a tumor.

They found that MPs in tissue from women less than 30 years old were extremely responsive to changes to their immediate surroundings. When tissue from young women was placed on a soft polymer, MPs differentiated into milk-producing luminal cells. When the tissue was placed on a stiff polymer, the cells reduced the production of luminal cells and ramped up the production of tumor-fighting myoepithelial cells.

But this defense wasn’t observed in tissue from women older than 55. Instead of responding to a stiff polymer by increasing the production of tumor-suppressing cells, MPs from older women produced equal amounts of luminal and tumor-suppressing cells. They also made more of themselves. That’s bad for a couple of reasons, the investigators said. Most cancers diagnosed in older women are luminal, and more MPs means more cells that can become cancerous.

“We found that as women age, multipotent progenitors, which are the cells responsible for maintaining healthy homeostasis in breast tissue, no longer respond to their microenvironment like they do in younger women,” said lead investigator Dr. Mark LaBarge.

“Our work shows that one reason for this is that multipotent progenitors in older tissue do not correctly perceive differentiation cues, such as the mechanical stiffness of their surroundings,” he added.

The scientists traced this failure to a breakdown in a cellular process that converts external mechanical cues — in this case, the stiffness of the tissue outside of the cell membrane — into an internal molecular message that tells the cell nucleus what to do. In MPs in women older than 55, the molecules that help deliver this message are inefficiently activated, the scientists found.

They believe this breakdown stems from changes in the way women’s genes are activated and silenced as they grow older.

Source: Berkeley Lab; June 5, 2014.

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