Researchers have identified the gene-regulating protein Runx3 as a potent suppressor of tumor growth in breast cancer and found that it most likely does this by regulating cellular response to circulating estrogen, the process behind estrogen-receptor positive (ER-positive) breast cancers, which account for over 70% of human breast cancers. They hope their discovery will lead to a biomarker test for early stage breast cancer and treatments that reactivate Runx3 to suppress tumor growth.
You can read how senior investigator Lin-Feng Chen, professor of medical biochemistry at the University of Illinois and other colleagues from the US, Singapore and Japan, identified the protein and found out how it works in the 27 June online issue of Oncogene.
The idea that Runx3 regulates gene expression and probably plays a role in breast cancer is not new, as Chen explained to the press:
“People suggested that Runx3 might be a tumor suppressor in breast cancer because they found that it is down-regulated in a lot of breast cancer cell lines and breast cancer tissues.”
Their investigation is the first to find strong evidence of how it does it.
First, they discovered that about 20% of female mice lacking one out of their possible two copies of the Runx3 gene spontaneously developed breast tumors when they reached the age of 14 or 15 months, which corresponds to about 40 or 50 years old in humans.
Then they found that the mouse tumors were overexpressing estrogen receptor alpha (ER-alpha), which is known to be involved in the development of about 75% of human breast cancers.
Over-expression of ER-alpha causes cells with these receptors to attract a lot more circulating estrogen than normal. Estrogen is an important hormone that once inside cells alters the expression of many other genes and the signals they send to make cells grow and work. However, above normal levels means that tumor cells are more likely to survive, grow and multiply.
Over-expression of ER-alpha in normal breast tissue is also a known risk factor for breast cancer, said Chen.
Working with cell lines, that is cultures of cells in test tubes, Chen and colleagues found that when they introduced Runx3 into ER-alpha positive breast cancer cells, it suppressed their growth.
And then, when they introduced those cancer cells into immunodeficient mice, they did not form tumors.
In further experiments they showed that Runx3 undermines the signals from ER-alpha by degrading the receptor.
Chen said that Runx3 appears to control cells’ responses to circulating estrogen by regulating cellular levels of ER-alpha, “thus playing an important role in the onset of breast cancer”.
The researchers said they hope their findings will help to develop a biomarker test for early stage breast cancer that checks for Runx3 activation, and perhaps also, future studies can find out how to reverse inactivation of Runx3 as a potential treatment.
“If you can reactivate Runx3, then you can suppress tumor growth,” said Chen.
Funds from the National Institutes of Health and the University of Illinois Campus Research Board paid for the study.
B Huang, Z Qu, C W Ong, Y-H N Tsang, G Xiao, D Shapiro, M Salto-Tellez, K Ito, Y Ito and L-F Chen.
Oncogene, advance online publication, 27 June 2011.
DOI:10.1038/onc.2011.252
Additional source: University of Illinois at Urbana-Champaign.
Written by: Catharine Paddock, PhD