Scientists discover how breast cancer cells become resistant to therapy

About a quarter of relapsed estrogen receptor positive (ER+) breast cancers lose ER expression, making them resistant to endocrine therapy and allowing them to grow uncontrollably. A team of researchers from Baylor College of Medicine has investigated how these cells lose their ER, and in the current study published in the Proceedings of the National Academy of Sciences, they reveal a mechanism that not only explains the process, but also provides opportunities to to overcome it.

“For years, our goal has been to unravel the complex puzzle of breast cancer progression to understand how the players interact to resist therapy and sustained growth,” said corresponding author Dr. Weei-Chin Lin, professor of medicine. – hematology and oncology and of molecular and cell biology at Baylor. “Our goal is to overcome this hurdle to restore ER receptor expression in these cancers, making them amenable to therapy again, giving patients a better chance of recovery.”

How breast cancer cells use their ER. losses

Two cellular proteins known as 14-3-3τ and ERα36 have previously been implicated in the development of breast cancer resistance to endocrine therapy.

“When we worked with a mouse model of human ER+ breast cancer, we were surprised to find that overexpression of 14-3-3τ in these tumors caused all cancer cells to become ER-negative (ER-),” said Lin, a member from the Dan L Duncan Comprehensive Cancer Center. “I still remember the day I saw the data. The change was dramatic – all tumors had lost their ER!”

Studying the mechanism in animal models would be laborious, 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 in the Lin lab, developed a spherical model of human breast cancer cells that mimics the progression from ER+ to ER- and provides a very useful experimental tool for future studies. research.

“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 spheroid lab 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, are also needed,” Garan said. “Importantly, we also found that factors produced by the tumor microenvironment, including fibroblasts and immune cells that make up the tumor mass and crosstalk with the cancer cells, are also essential for the progression from ER+ to ER-.”

“We knew that 14-3-3τ, ERα36, AKT and GATA3 were the key players involved in converting ER+ breast cancer cells into ER cells. Here we determined how they functionally interact with each other, by creating a map of the pathway leading to ER loss,” said Lin. “I am very excited that with our spheroid breast cancer model we now have a valuable tool to not only to study cellular changes involved in breast cancer progression, as well as to test drugs for their ability to inhibit the process leading to ER loss.”

“The protein 14-3-3τ is overexpressed in about 60% of breast cancers. Not all patients with high 14-3-3τ will lose the ER, but for those who do, our findings may one day help their tumors recover 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 of 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 Department of Defense grants W81XWH-18-1-0329 and W81XWH-19-1-0369.

About a quarter of relapsed estrogen receptor positive (ER+) breast cancers lose ER expression, making them resistant to endocrine therapy and allowing them to grow uncontrollably. A team of researchers from Baylor College of Medicine has investigated how these cells lose their ER, and in the current study published in the Proceedings of the National Academy of Sciences, they reveal a mechanism that not only explains the process, but also provides opportunities to to overcome it.

“For years, our goal has been to unravel the complex puzzle of breast cancer progression to understand how the players interact to resist therapy and sustained growth,” said corresponding author Dr. Weei-Chin Lin, professor of medicine. – hematology and oncology and of molecular and cell biology at Baylor. “Our goal is to overcome this hurdle to restore ER receptor expression in these cancers, making them amenable to therapy again, giving patients a better chance of recovery.”

How breast cancer cells use their ER. losses

Two cellular proteins known as 14-3-3τ and ERα36 have previously been implicated in the development of breast cancer resistance to endocrine therapy.

“When we worked with a mouse model of human ER+ breast cancer, we were surprised to find that overexpression of 14-3-3τ in these tumors caused all cancer cells to become ER-negative (ER-),” said Lin, a member from the Dan L Duncan Comprehensive Cancer Center. “I still remember the day I saw the data. The change was dramatic – all tumors had lost their ER!”

Studying the mechanism in animal models would be laborious, 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 in the Lin lab, developed a spherical model of human breast cancer cells that mimics the progression from ER+ to ER- and provides a very useful experimental tool for future studies. research.

“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 spheroid lab 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, are also needed,” Garan said. “Importantly, we also found that factors produced by the tumor microenvironment, including fibroblasts and immune cells that make up the tumor mass and crosstalk with the cancer cells, are also essential for the progression from ER+ to ER-.”

“We knew that 14-3-3τ, ERα36, AKT and GATA3 were the key players involved in converting ER+ breast cancer cells into ER cells. Here we determined how they functionally interact with each other, by creating a map of the pathway leading to ER loss,” said Lin. “I am very excited that with our spheroid breast cancer model we now have a valuable tool to not only to study cellular changes involved in breast cancer progression, as well as to test drugs for their ability to inhibit the process leading to ER loss.”

“The protein 14-3-3τ is overexpressed in about 60% of breast cancers. Not all patients with high 14-3-3τ will lose the ER, but for those who do, our findings may one day help their tumors recover 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 of 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 Department of Defense grants W81XWH-18-1-0329 and W81XWH-19-1-0369.

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