Mistaken antibodies may have led breast cancer research down a 20-year dead end

June 15, 2017, KTH Royal Institute of Technology
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). Credit: the Human Protein Atlas

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

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

Cecilia Williams, a researcher at KTH Royal Institute of Technology in Stockholm and the joint research center, Science for Life Laboratory (SciLifeLab), says the beta receptor's discovery changed our 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 (ESR1), which was the first and most important biomarker in , and can predict which patients respond to anti-estrogen treatment.

But about half of such breast tumors do not respond to anti-estrogen therapies, or they develop resistance over time, Williams says. "It has been thought that ERS2 had an opposite effect to ERS1, 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 ERbeta in – efforts that our study suggests are based on inadequate data," she says. "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."

The Sweden-based research team says their study invalidates all but one of the antibodies used to detect estrogen receptor beta. These 12 antibodies have instead been mistaking other proteins for ESR2, Williams says, and data generated with these antibodies cannot be trusted.

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

Also estrogen research relating to multiple other tissues and diseases are impacted by this study. Many false leads over the years may be due to "insufficiently specific" antibodies in the field of immunohistochemistry (IHC), Williams says.

The researchers validated the antibodies with a level of unprecedented rigor, she says. The team, which included researchers from Uppsala University and Karolinska Institute, used negative and positive controls and applied multiple antibody-based applications. They compared performance of different antibodies on 44 different human tissue types and further identified bound proteins through techniques such mass spectroscopy at a scale not before undertaken.

They also searched large databases of gene expression, including The Cancer Genome Atlas, The Genotype-Tissue Expression, and the Human Protein Atlas, and pin-pointed a universal lack of beta messenger RNA in breast tissue.

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

Anna Asplund, a researcher with Uppsala University, says the work should bring attention to a timely topic. "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."

In addition to the Swedish research universities, the research involved the Division of Pharmaceutical Industries, National Research Centre, in Dokki, Egypt; and the Department of Biology and Biochemistry, University of Houston, Texas, USA.

The project was supported by grants from the National Cancer Institute at the National Institutes of Health, Marie Curie Actions via the Swedish Governmental Agency for Innovation Systems (VINNOVA), the Swedish Cancer Society, the Stockholm County Council, the Swedish Research Council, and the Knut and Alice Wallenberg Foundation.

Explore further: Exposure to BPA substitute, BPS, multiplies breast cancer cells

More information: Sandra Andersson et al, Insufficient antibody validation challenges oestrogen receptor beta research, Nature Communications (2017). DOI: 10.1038/ncomms15840

Related Stories

Exposure to BPA substitute, BPS, multiplies breast cancer cells

April 2, 2017
Bisphenol S (BPS), a substitute for the chemical bisphenol A (BPA) in the plastic industry, shows the potential for increasing the aggressiveness of breast cancer through its behavior as an endocrine-disrupting chemical, ...

Prevalence of estrogen receptor mutations in patients with metastatic breast cancer

August 11, 2016
A new study published online by JAMA Oncology examines the prevalence and significance of estrogen receptor mutations in patients with metastatic breast cancer.

New insights into mechanisms of breast cancer development and resistance to therapy

January 9, 2017
Why does breast cancer develop and how come certain patients are resistant to established therapies? Researchers from the University of Basel have gained new insights into the molecular processes in breast tissue. They identified ...

Researchers discover key to drug resistance in common breast cancer treatment

March 20, 2017
Three-quarters of all breast cancer tumors are driven by the hormone estrogen. These tumors are frequently treated with drugs to suppress estrogen receptor activity, but unfortunately, at least half of patients do not respond ...

Breast cancer study predicts better response to chemotherapy

December 15, 2016
It is known from previous research that the ER-beta estrogen receptor often has a protective effect. A new study from Lund University in Sweden has found that this effect is more pronounced in patients that undergo chemotherapy.

Possible new weapon found for fighting some types of breast cancer

June 23, 2014
Researchers believe they have discovered one reason why some women with estrogen receptor-positive breast cancer may respond poorly or only temporarily to estrogen-blocking drugs such as tamoxifen. Results of a new study, ...

Recommended for you

Stem cell vaccine immunizes lab mice against multiple cancers

February 15, 2018
Stanford University researchers report that injecting mice with inactivated induced pluripotent stem cells (iPSCs) launched a strong immune response against breast, lung, and skin cancers. The vaccine also prevented relapses ...

Induced pluripotent stem cells could serve as cancer vaccine, researchers say

February 15, 2018
Induced pluripotent stem cells, or iPS cells, are a keystone of regenerative medicine. Outside the body, they can be coaxed to become many different types of cells and tissues that can help repair damage due to trauma or ...

Team paves the way to the use of immunotherapy to treat aggressive colon tumors

February 15, 2018
In a short space of time, immunotherapy against cancer cells has become a powerful approach to treat cancers such as melanoma and lung cancer. However, to date, most colon tumours appeared to be unresponsive to this kind ...

Can our genes help predict how women respond to ovarian cancer treatment?

February 15, 2018
Research has identified gene variants that play a significant role in how women with ovarian cancer process chemotherapy.

First comparison of common breast cancer tests finds varied accuracy of predictions

February 15, 2018
Commercially-available prognostic breast cancer tests show significant variation in their abilities to predict disease recurrence, according to a study led by Queen Mary University of London of nearly 800 postmenopausal women.

Catching up to brain cancer: Researchers develop accurate model of how aggressive cancer cells move and spread

February 15, 2018
A brief chat at a Faculty Senate meeting put two University of Delaware researchers onto an idea that could be of great value to cancer researchers.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.