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barbara
04-12-2010, 03:51 PM
Posted by Megan Scudellari
11th April 2010


Estrogen and progesterone promote the proliferation and activity of mouse mammary stem cells, according to new research published online today (April 11) at Nature -- possibly explaining the link between exposure to the hormones and breast cancer.

"It's a pretty good paper," said John Stingl, a researcher at the Cancer Research UK Cambridge Research Institute, who did not participate in the study. In a very direct way, the researchers have successfully measured the effects of progesterone and estrogen on mammary stem cells, he said.

Estrogen and progesterone levels have profound effects on breast development and breast cancer risk. There is a clear correlation between number of menstrual cycles (and thus lifetime exposure to these hormones) and breast cancer risk, for example, and therapeutic regimens that inhibit the binding or synthesis of estrogen reduce the rate of breast cancer recurrence for some patients by almost half. The mechanism by which these hormones work, however, remains elusive, said Stingl.

One possible role is their effects on mammary stem cells (MaSCs), whose highly proliferative abilities make them suspects as causative agents in breast cancer. But there was no proof that MaSCs respond to hormones, Stingl said. And there was a major theoretical problem: MaSCs lack receptors for both hormones. The question then became, is it possible that cells with no receptors for progesterone or estrogen are still affected by their presence?

To find out, Jane Visvader of the Walter and Eliza Hall Institute in Victoria, Australia, and her colleagues tested the activity of MaSCs in the absence of estrogen and progesterone. Removing the ovaries from young adult mice, the researchers saw a significant decrease in the number of mammary stem cells. Conversely, treating young mice with estrogen and progesterone pellets to expose them to far greater levels of hormones than normal, the team recorded an increase in the number of stem cells. Together, these results suggest the hormones do indeed promote MaSC growth.

Visvader and her colleagues also assessed the size of MaSC populations during pregnancy and found an eleven-fold increase in the number of stem cells in the mammary glands during mid-pregnancy -- when females have highly elevated levels of progesterone -- compared to glands from virgin mice. The finding coincides with the observation that women have an increased risk of developing breast cancer for a short period following pregnancy. "This increase in the number of mammary stem cells [during pregnancy] provides a tantalizing mechanism to account for that [increased risk]," said Visvader.

One concern is that what the researchers thought were MaSCs may actually have been other cell types, said Cathrin Brisken, a breast cancer researcher at the Ecole Polytechnique F?d?rale in Lausanne, Switzerland. "The paper makes claims that are very reasonable, but doesn't provide the data for it," said Brisken. Accurately identifying and counting MaSCs requires rigorous assays, she said, and "one has to be really careful of whether given markers really identify a stem cell population."

To address this concern, the researchers injected the suspected MaSCs into a fat pad to demonstrate the cells' capacity to grow into new mammary glands in vivo -- the gold standard for identifying MaSCs. Additionally, mice exposed to estrogen and progesterone grew fuller mammary glands than mice lacking ovaries, demonstrating increased activity of the transplanted MaSCs in the presence of the hormones. "The heart of the paper is the transplants," Stingl said, "and they've done those."

But how progesterone and estrogen stimulate MaSC growth and activity is still unknown. Researchers suspect the effect occurs through paracrine signaling: Cells with progesterone and estrogen receptors sense the hormones, and then release a signal to the nearby stem cells. Visvader and her team identified one possible signal, RANKL, a ligand important for mouse mammary gland development, that seems to affect MaSC expansion during pregnancy, but "the whole system is not quite worked out yet," said Stingl.