Studying the mechanism in animal models would be labor intensive, time consuming and expensive, so the researchers developed an alternative model. First author Lidija A. Wilhelms Garan, a student in Baylor’s Cancer and Cell Biology Graduate Program working in the Lin lab, developed a spheroid model of human breast cancer cells that mimics the progression from ER+ to ER- and provides a very useful experimental tool for future investigation.
“In a patient, a breast tumor can take years to progress from ER+ to ER-, in our animal model it takes several months but in our spheroid model it switches from ER+ to ER- in 1 to 2 weeks,” Garan said.
In the lab spheroid model the team found that once 14-3-3τ is over-expressed in cancer cells under the right conditions, the cells will increase their levels of ERα36 and this is followed by ER loss.
“Other molecular players, such as AKT and GATA3, also are required,” Garan said. “Importantly, we also found that factors produced by the tumor microenvironment, which includes fibroblasts and immune cells that are part of the tumor mass and cross talk with the cancer cells, also are essential for the progression from ER+ to ER-.”
“We knew that 14-3-3τ, ERα36, AKT and GATA3 were the key players involved in turning ER+ breast cancer cells into ER- cells. Here we have determined how they functionally interact with each other, laying out a map of the road that leads to ER loss,” Lin said. “I am very excited that with our spheroid breast cancer model we now have a valuable tool to study not only the cellular changes involved in breast cancer progression but also to test drugs for their ability to inhibit the process that leads to ER loss.”
“The protein 14-3-3τ is overexpressed in about 60% of breast cancers. Not all patients that have high 14-3-3τ will lose the ER, but for those who do, our findings may one day help restore their tumors to a therapy-sensitive state,” Garan said. “The translational aspect of this research has always been close to my heart – to bring discoveries to the clinic and improve people’s lives.”
Yang Xiao at Baylor College of Medicine was also an author of this work.
This work was supported by NIH Grants R01CA203824, R01CA100857, R21CA198041, T32GM136560 and T32CA174647 and the Department of Defense Grants W81XWH-18-1-0329 and W81XWH-19-1-0369.
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