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Researchers have figured out why breast cancer cells resist treatment

by Vaishali Sharma
breast

Because one-fourth of recurrent oestrogen receptor-positive (ER+) breast cancers lack ER expression, they are resistant to endocrine therapy and can spread uncontrollably.

A recent study published in the Proceedings of the National Academy of Sciences by a group of Baylor College of Medicine researchers reveals a mechanism that not only explains the process but also suggests ways to avoid it.

“For years, our goal has been to piece together the complex puzzle of breast cancer progression to understand how the players interact with one another to confer resistance to therapy and persistent growth,” said corresponding author Dr Weei-Chin Lin, a Baylor professor of medicine-haematology and oncology as well as molecular and cellular biology.

“Our goal is to overcome this barrier and restore ER receptor expression in these cancers so they can be treated again, giving patients a better chance of survival.”

The process by which breast cancer cells lose their ER

Resistance to endocrine therapy in breast cancer has previously been linked to two cellular proteins known as 14-3-3 and ER-36.

“We were surprised to find that over-expressing 14-3-3t in these tumours resulted in all of the cancer cells becoming ER-negative (ER-),” said Lin, a member of the Dan L Duncan Comprehensive Cancer Center. “I recall seeing the data for the first time. The transformation was dramatic: all of the tumours had lost their ER!”

Because studying the mechanism in animal models would be laborious, time-consuming, and costly, the researchers devised an alternative model. Lidija A., the first author,

Wilhelms Garan, a graduate student in Baylor’s Cancer and Cell Biology Graduate Program who works in the Lin lab, created a spheroid model of human breast cancer cells that mimics the progression from ER+ to ER- and serves as a useful experimental tool for future research.

“A breast tumour in a patient 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 explained.

The researchers discovered that when 14-3-3t is over-expressed in cancer cells under the right conditions, the cells increase their levels of ERa36, which is followed by ER loss.

“Other molecular players like AKT and GATA3 are also required,” Garan explained. “Most importantly, we discovered that factors produced by the tumour microenvironment, which includes fibroblasts and immune cells that are part of the tumour mass and interact with cancer cells, are also required for the progression from ER+ to ER-.”

“Other molecular players like AKT and GATA3 are also required,” Garan explained. “Most importantly, we discovered that factors produced by the tumour microenvironment, which includes fibroblasts and immune cells that are part of the tumour mass and interact with cancer cells, are also required for the progression from ER+ to ER-.”

“We knew 14-3-3t, ERa36, AKT, and GATA3 were key players in the transformation of ER+ breast cancer cells to ER- cells.” “Here, we’ve determined how they functionally interact with one another, laying out a road map that leads to ER loss,” Lin explained.

“I am very excited that we now have a valuable tool with our spheroid breast cancer model 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.”

“In approximately 60% of breast cancers, the protein 14-3-3t is overexpressed. Not all patients with high 14-3-3t will develop the ER, but for those who do, our findings may one day aid in returning their tumours to a therapy-sensitive state “Garan stated. “Bringing discoveries to the clinic and improving people’s lives has always been a passion of mine in this research.”

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