Researchers Uncover How Resistance to Treatment Can Develop in Breast Cancer Cells
Tumor cells can develop resistance to endocrine therapy, a major obstacle limiting the success of breast cancer treatment. The complicated crosstalk, both genomic and nongenomic, between estrogen receptors and growth factors, was considered to be a crucial factor contributing to endocrine resistance. A new study in mice by researchers at Baylor College of Medicine has investigated how these cells lose their estrogen receptor–positive (ER+) expression. Their findings reveal a mechanism that explains the process and potential possibilities to overcome it.
“About one-fourth of recurrent estrogen receptor–positive (ER+) breast cancers lose ER expression, leading to endocrine therapy failure,” wrote the researchers. “However, the mechanisms underlying ER loss remain to be fully explored. We now show that 14-3-3τ, up-regulated in ∼60% of breast cancer, drives the conversion of ER+ to ER– and epithelial-to-mesenchymal transition (EMT).”
“For years, our goal has been to tease out the complex puzzle of breast cancer progression to understand how the players interact with each other to confer resistance to therapy and persistent growth,” said corresponding author Weei-Chin Lin “Our goal is to overcome this hurdle to restore ER receptor expression in these cancers so they become susceptible to therapy again, giving patients a better chance for recovery.”
Two cellular proteins known as 14-3-3τ and ERα36 have been previously implicated in the development of breast cancer resistance to endocrine therapy.
Studying the mechanism in animal models would be labor-intensive, time-consuming, and expensive, so the researchers developed an alternative model. Lidija A. Wilhelms Garan developed a spheroid model of human breast cancer cells that mimics the progression from ER+ to ER- and provides a 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 overexpressed 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-”.
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