“Estrogen-receptor alpha (ER) positive breast cancers constitute 70 percent of all breast cancer cases, and these cancers depend on estrogen for growth,” said Dr. Wei Xu, professor of oncology at the UW School of Medicine and Public Health and senior author of the study.
She added that ER-positive breast cancers are typically treated with endocrine therapy such as tamoxifen, but some cancers can develop resistance to therapy over time.
“In this study we sought to identify novel components that regulate the estrogen response,” Xu said. “We found that a single protein, Ctr9, could control the majority of ER-targeted genes and, therefore, could play a large role in ER-regulated breast cancer.”
Xu and her co-author, graduate student Hao Zeng, first identified elevated Ctr9 levels as being correlated with those of ER in breast cancers by mining gene expression data from many previously published studies. They also found that high levels of Ctr9 were associated with poor survival among all women with ER-positive breast cancers, and specifically among those treated with tamoxifen.
Next, they wanted to know what role Ctr9 plays in breast cancer cells. To do so, they depleted Ctr9 from ER-positive cancer cells, then measured gene expression changes in those cells in response to estrogen treatment.
“We found that over 1,600 genes are regulated by estrogen treatment, and of those 1,600, only 50 genes respond to estrogen after Ctr9 knockdown,” Xu said. “In other words, if you lost Ctr9, you nearly wipe out the estrogen response in cells.”
Perhaps most significantly, ER itself was found at greatly reduced levels when Ctr9 was knocked down, further implicating Ctr9’s role in aiding ER-positive breast cancers to develop resistance to endocrine therapy. Based on this study, Xu says that, short-term, Ctr9 levels in breast cancers could be measured to better predict a patient’s response to ER-targeting therapies.
“More importantly, Ctr9 could be a therapeutic target,” she added. “In our basic study we’ve shown Ctr9 is very important for ER-mediated responses, so finding therapies that inhibit Ctr9 could be an effective way to turn off estrogen-dependent tumor growth.”
Xu noted that Ctr9 is not the first protein to be implicated in endocrine therapy-resistant breast cancer, but stressed the importance of its identification here.
“Ctr9 is near the top of the estrogen response hierarchy, and we found that many of the known players conferring tamoxifen resistance are regulated by Ctr9. It’s a ‘master regulator’ of the response,” Xu said.
The study was published in Genes and Development.
University of Wisconsin School of Medicine and Public Health