Swedish Study Rules 20 Years of Cancer Research Futile

15/06/2017 - 3 minutes

The role of the ERβ receptor in breast cancer has been debated for 20 years. Now, a new study suggests that researchers have analyzed the wrong protein.

Since its discovery about 20 years ago, researchers have sought to understand the role of the estrogen receptor beta (ERβ)  in breast cancer. However a new study led by researchers at the KTH Royal Institute of Technology in Stockholm questions whether reliance on insufficiently validated antibodies has misled scientists for almost two decades.

In a study published in Nature Communications today, a team around Cecilia Williams, a researcher at KTH, has invalidated all but one of 13 commercially available or in-house antibodies used to detect the ERβ protein. These 12 antibodies have instead been mistaking other proteins for ERβ, Williams explains, indicating that all data generated with these antibodies cannot be trusted.

The researchers studied the performance of the different antibodies on 44 different human tissue types and further identified bound proteins using mass spectrometry. Ironically, the one antibody that actually binds the ERβ receptor, cannot find any trace of the receptor in healthy or in cancerous breast tissue. The data was also compared to RNA sequencing data from large databases such as the Cancer Genome Atlas, which confirmed the lack of ERβ mRNA in breast tissue.

Preceding ERβ, the estrogen receptor alpha (ERα) was the first biomarker that was applied in oncology. The receptor is expressed by more than 70% of breast cancers and its inhibition remains one of the most efficacious treatments for ERα-positive breast cancers to date.

A closeup look at four cancerous tissues shows no estrogen receptor beta (ERS2) in the breast tumor (lower left), nor in one of two samples of granulosa cell tumors (top right). Arrows point to the ERS2 in another granulosa tumor sample (upper left) and a thyroid tumor (lower right).

Yet, about 40% of the ERα-positive breast cancers fail to respond or develop resistance to endocrine treatment, which is why the identification of the second estrogen receptor, ERβ, was met with massive interest for its potential as a new complementary biomarker and therapeutic target in breast cancer.

However, after 20 years of research, the role of ERβ and even its distribution are still unclear and debated. “It has been thought that ERβ had an opposite effect to ERα, and that the beta receptor should not be blocked, but instead activated in breast cancer. This would supposedly improve survival,” commented Cecilia Williams, a researcher at KTH Royal Institute of Technology in Stockholm.

According to Williams, clinical studies are currently ongoing, to activate ERβ in patients with breast cancer; “efforts that our study suggests are based on inadequate data,” she says.

“Significant problems due to poor validation of antibodies have recently been brought to the headlines by major journals, including Nature. We hope that our study, together with other on-going antibody validation efforts, will lead to a better quality of antibodies and antibody-based research,” concludes Anna Asplund, who supervised the study.

At a time where antibodies make up and integral part of biomedical research, we can only hope that this is not a universal problem.

Images via shutterstock.com / molekuul_be and proteinatlas.org


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