Mistaken Antibodies May Have Led Cancer Research Down a 20-Year Dead End

Study suggests receptor antibodies are “insufficiently specific”

For nearly two decades, researchers have sought a way to target an estrogen receptor in the hope that they could improve breast cancer survival, but an article published in Nature Communications contends that the effort may never pan out. The reason? The target receptor doesn’t appear to be where scientists thought it was.

The new study questions whether the reliance on insufficiently validated antibodies has led science down a dead-end path since the discovery of estrogen receptor 2 (ESR2) in the 1990s.

Dr. Cecilia Williams, professor of experimental oncology at the KTH Royal Institute of Technology in Stockholm, said the beta receptor’s discovery changed researchers’ understanding of estrogen signaling. It also raised hopes for a new endocrine treatment to complement the success of estrogen-blocking drugs, such as tamoxifen.

These therapies target estrogen receptor alpha (ESR1), which was the first and most important biomarker in breast cancer, and can predict which patients will respond to anti-estrogen treatment. But approximately half of such breast-cancer tumors do not respond to anti-estrogen therapies, or they develop resistance over time, Williams said. “It has been thought that ESR2 had an opposite effect to ESR1 [alpha], and that the beta receptor should not be blocked but instead activated in breast cancer. This would supposedly improve survival.”

“Clinical trials are ongoing in the world right now, which activate ESR beta in breast cancer patients––efforts that our study suggests are based on inadequate data,” she said. “While we cannot claim that this receptor is completely absent in breast tumors, we do challenge the data behind the notion that the receptor is there.”

Williams’ research team said their study invalidates all but one of 12 antibodies used to detect ESR2. These antibodies have been mistaking other proteins for ESR2, Williams said, and data generated with them cannot be trusted.

The one remaining antibody that can successfully be used against the ESR2 receptor, however, can find no trace of the receptor in cancerous or healthy breast tissue, the study found.

Estrogen research related to other tissues and diseases are affected by this study, Williams said. In her opinion, many false leads over the years may be due to “insufficiently specific” antibodies in the field of immunohistochemistry.

 “Our study contributes to improved reproducibility within research using biologics, or antibodies, and it clarifies earlier controversies within the field of estrogen and breast cancer, thus helping move the field forward. In the end, we hope our study will help save both research funding and research time,” she said.

Source: KTH Royal Institute of Technology; June 15, 2017.