Dietary xenoestrogens may reduce effectiveness of breast cancer treatment

Scientists have discovered that two estrogen-mimicking compounds found in many foods appear to potently reverse the effects of palbociclib/letrozole, a popular drug combination for treating breast cancer.

Cancer researchers are increasingly concerned that xenoestrogens in food and water may enhance the growth of estrogen-fueled cancers, and may also hamper the effectiveness of anti-estrogen drugs such as letrozole. The Scripps Research Institute (TSRI) scientists, therefore, examined breast cancer cells treated with palbociclib/letrozole to see how their metabolite populations changed when they were also exposed to two common dietary xenoestrogens: zearalenone and genistein.

Breast cancer patients taking palbociclib/letrozole should consider limiting their exposure to foods that contain xenoestrogens

Zearalenone is produced by fungi that colonise maize, barley, wheat and other grains. It has been linked to birth defects and abnormal sexual development in pigs and other livestock and is suspected of having caused an outbreak of early breast development among girls in Puerto Rico in the 1970s. Genistein is produced in certain plants including soybeans and is often highly concentrated in phytoestrogen-rich food supplements.

Even using very low doses, similar to typical dietary exposures, the researchers found that both model xenoestrogens largely reversed the metabolomic impact of the cancer drug combination. "This included many key metabolites," says Dr Gary Siuzdak the study’s senior author and senior director of TSRI’s Scripps Center for Metabolomics.

Under the influence of either xenoestrogen, the breast cancer cells also resumed proliferating at a rate comparable to that seen in the absence of drug treatment.

"Breast cancer patients taking palbociclib/letrozole should consider limiting their exposure to foods that contain xenoestrogens," says Dr Siuzdak.

Dr Siuzdak and colleagues, including first and lead author Dr Benedikt Warth, then a visiting Erwin-Schrödinger Fellow in the Siuzdak Lab, used advanced metabolomics technology to analyse the effects of palbociclib/letrozole on breast cancer cells. Metabolomics studies detail cells’ metabolomes–populations of metabolites, the small-molecule end products of cellular processes.

"By profiling cell metabolomes with and without drug treatment we can get very useful information, for example about the biological pathways perturbed by the drug," says Dr Siuzdak.

Their analysis revealed that neither palbociclib alone nor letrozole alone had a strong effect on metabolites in an ER-positive breast cancer cell line. However, the combination had a strikingly large impact. "The combination had a much more pronounced effect on cell-growth-related metabolites, which is consistent with the clinical trial results," Dr Warth says.

"It’s intriguing that even a low, background-level exposure to these xenoestrogens was enough to impact the effect of the therapy to this degree," says Prof Warth, who is now an Assistant Professor at the University of Vienna’s Department of Food Chemistry & Toxicology.

The results indicate that these dietary xenoestrogens do have the potential to affect cancer therapy outcomes–and genistein and zearalenone are just two of the many xenoestrogens commonly found in the human diet. "There’s a high likelihood that other xenoestrogens would counteract the therapy in a similar way," Dr Siuzdak says.

The impact of xenoestrogens on health and on hormonally-targeted therapies is nevertheless an understudied, underfunded area of research, the researchers emphasized.

"We generally know very little about the interactions of bioactive compounds we are exposed to through our food or the environment with drug treatments," Dr Warth says. "So, in this field, there are probably a lot of clinically relevant discoveries yet to be made."

"What I find intriguing is that metabolomics can be used to identify active metabolites that are therapeutically beneficial or, as in this case, exogenous fungal and plant metabolites that are detrimental," Dr Siuzdak says. "Clearly, metabolites can have a significant impact in modulating therapeutics."

The research has been published in the journal Cell Chemical Biology.