Discovery halts breast cancer stem cells

November 23, 2010, Tufts University

Breast cancer stem cells (CSCs), the aggressive cells thought to be resistant to current anti-cancer therapies and which promote metastasis, are stimulated by estrogen via a pathway that mirrors normal stem cell development. Disrupting the pathway, researchers were able to halt the expansion of breast CSCs, a finding that suggests a new drug therapy target. The study, done in mice, is published in the Proceedings of the National Academy of Sciences (PNAS) Early Edition this week.

"A critical aspect of our work was to discover that could promote growth by modulating the proportion of breast CSCs. Since CSCs were not directly sensitive to estrogen, it wasn't clear how estrogen could affect their numbers. However, we found that hormone-sensitive cancer cells can communicate with CSCs to regulate their numbers. By disrupting the interaction between cancer cell populations we were able to prevent tumor growth," said Charlotte Kuperwasser, PhD, associate professor in the anatomy and cellular biology and radiation oncology departments at Tufts University School of Medicine, and member of the genetics and cell, molecular & developmental biology program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts.

"Interestingly, this signaling pathway involves many of the same players that control normal stem cell biology, raising a more general possibility that CSCs in other tumors might be regulated by the mechanisms guiding normal development," said Kuperwasser.

Kuperwasser and colleagues from MIT and Harvard used a mouse model to examine the behavior of cancerous human breast tissue with a method that mimics the human body more closely than standard mouse models. The researchers first examined estrogen's effect on breast CSC growth, finding that estrogen caused breast CSC numbers to increase by nearly 800 percent. Since few breast CSCs contain estrogen receptors, the researchers suspected that estrogen's actions were through a signaling mechanism from nearby cells that express the receptors.

"When nearby cells were exposed to estrogen, they secreted 14 times more FGF9, a signaling protein that drives CSC proliferation. When we blocked the FGF pathway with a small molecule inhibitor, we saw loss of CSC growth, tumorspheres generation, and even tumor formation. We then linked FGF signaling to the Tbx3 signaling axis, which is also important for embryonic mammary gland development," said first author Christine Fillmore, PhD, a 2009 graduate of the genetics program at the Sackler School and currently a research fellow in genetics at Children's Hospital Boston.

"These results show that interfering with this signaling pathway is a promising strategy for targeting breast CSCs. We are hopeful that the improved understanding of the mechanisms that promote breast CSCs will lead to the development of drugs that can be used to halt CSC proliferation," said Kuperwasser.

Kuperwasser also leads a laboratory at the Molecular Oncology Research Institute (MORI) at Tufts Medical Center, which is dedicated to the exploration of the molecular mechanisms of cancer and the translation of findings into the clinic.

More information: Fillmore CM, Gupta PB, Rudnick JA, Caballero S, Keller PJ, Lander ES, and Kuperwasser C. PNAS Early Edition. "Estrogen expands breast cancer stem-like cells through paracrine FGF/Tbx3 signaling." Published online November 22, 2010 , doi:10.1073/pnas.1007863107

Related Stories

Recommended for you

'Hijacker' drives cancer in some patients with high-risk neuroblastoma

January 23, 2018
Researchers have identified mechanisms that drive about 10 percent of high-risk neuroblastoma cases and have used a new approach to show how the cancer genome "hijacks" DNA that regulates other genes. The resulting insights ...

Enzyme inhibitor combined with chemotherapy delays glioblastoma growth

January 23, 2018
In animal experiments, a human-derived glioblastoma significantly regressed when treated with the combination of an experimental enzyme inhibitor and the standard glioblastoma chemotherapy drug, temozolomide.

Scientists block the siren call of two aggressive cancers

January 23, 2018
Aggressive cancers like glioblastoma and metastatic breast cancer have in common a siren call that beckons the bone marrow to send along whatever the tumors need to survive and thrive.

Researchers identify a protein that keeps metastatic breast cancer cells dormant

January 23, 2018
A study headed by ICREA researcher Roger Gomis at the Institute for Research in Biomedicine (IRB Barcelona) has identified the genes involved in the latent asymptomatic state of breast cancer metastases. The work sheds light ...

Workouts may boost life span after breast cancer

January 22, 2018
(HealthDay)—Longer survival after breast cancer may be as simple as staying fit, new research shows.

Boosting cancer therapy with cross-dressed immune cells

January 22, 2018
Researchers at EPFL have created artificial molecules that can help the immune system to recognize and attack cancer tumors. The study is published in Nature Methods.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.