Hormones promote stem cell growth

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. Microphotography of a preparationof a healthy mammary gland Image: Wikimedia commons, linkurl:Luis A. Pardo et al.;http://commons.wikimedia.org/wiki/File:Healthy_mammary_gland.jpg "It's a pretty good paper,"

By | April 11, 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.
Microphotography of a preparation
of a healthy mammary gland

Image: Wikimedia commons,
linkurl:Luis A. Pardo et al.;http://commons.wikimedia.org/wiki/File:Healthy_mammary_gland.jpg
"It's a pretty good paper," said linkurl:John Stingl,;http://www.cambridgecancer.org.uk/research/loc/cambridge/ccri/stinglj/?view=CRI&source=research 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, linkurl:Jane Visvader;http://www.wehi.edu.au/faculty_members/dr_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 linkurl:Cathrin Brisken,;http://www.nccr-oncology.ch/scripts/index.aspx?idd=85 a breast cancer researcher at the Ecole Polytechnique Fédérale 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.
**__Related stories:__***linkurl:Cancer's culprit;http://www.the-scientist.com/article/display/55537/
[1st April 2009]*linkurl:Clearing estrogen's bad name;http://www.the-scientist.com/article/display/55138/
[11th November 2008]*linkurl:A case of mistaken identity;http://www.the-scientist.com/news/display/55013/
[16th September 2008]

Comments

Avatar of: Paul Knoepfler

Paul Knoepfler

Posts: 6

April 12, 2010

I think the authors' theory that an increase in normal MaSC during pregnancy is a causal event in increased breast cancer risk is total speculation. It's a very interesting idea, but the paper just doesn't address it at all. \n\nUnless I missed it the authors also do not discuss that fact that pregnancy is protective overall against breast cancer and probably against recurrence. How do they explain that?\n\nPaul\nhttp://stem.ws/blog.php
Avatar of: Hongrong Cai, MD

Hongrong Cai, MD

Posts: 14

April 13, 2010

Hormone promotes stem cell growth shouldn't be a surprise though it's an interesting topic. \n\nA few years ago, together with Dr Priscilla Furth(http://explore.georgetown.edu/people/paf3/) we used Tag transgenic mouse to explore estrogen and progesterone signaling pathway on breast cancer oncogenesis. (Loss of Stat5a delays mammary cancer progression in a mouse model, Oncogene. 2002 Jun 20;21(27):4335-9.) Now we all are aware that there is triple negative breast cancer (Estrogen receptor, progesterone receptor, Her2). At this moment maybe we can only say immunoescape is critical.

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