Dietary Estrogens Have Potential To Affect Cancer Outcomes Interview with:

Benedikt Warth, PhD, Assistant Professor Department of Food Chemistry and Toxicology University of Vienna Vienna, Austria 

Dr. Warth

Benedikt Warth, PhD, Assistant Professor
Department of Food Chemistry and Toxicology
University of Vienna
Vienna, Austria What is the background for this study?

Response: The palbociclib/letrozole combination therapy was granted accelerated approval by the U.S. Food and Drug Administration in 2015 after a clinical trial showed it doubled the progression-free survival time in postmenopausal women with estrogen receptor (ER) positive, metastatic breast cancer. Letrozole blocks the production of estrogen, thus reducing the growth-promoting stimulation of ERs on breast cancer cells. Palbociclib blocks a different signaling pathway to impede cell division. The combination is now one of the standard therapies for ER-positive breast cancers.

The aim of our study was twofold:

Firstly, we investigated the drugs synergism at the metabolome level in MCF-7 cells to unravel the unknown underlying metabolic effects of palbociclib/letrozole mechanism of action. We used a global metabolomics approach to analyze the effects of palbociclib and letrozole individually and in combination on breast cancer cells. Metabolomics studies detail cells’ metabolomes—populations of metabolites, the small-molecule end products of cellular processes.

Secondly, we aimed at deciphering the impact of the two model xenoestrogens frequently present in our diet, zearalenone and genistein, on this chemotherapy. Since these chemicals interact with the estrogen receptor we hypothesized that they may interfere with the new treatment. What are the main findings? 

Response: Our 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 which is consistent with the clinical trial results. With regard to the impact of dietary xenoestrogens on the combination therapy we found that both model xenoestrogens largely reversed the metabolomic impact of the cancer drug combination. 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. The results indicate that these dietary xenoestrogens may have the potential to affect cancer therapy outcomes – and genistein and zearalenone are just two of the many xenoestrogens potentially found in the human diet. Based on the mode of action there’s a high likelihood that other xenoestrogens would counteract the therapy in a similar way. What should readers take away from your report?

Response: Generally speaking: Food matters and can have an effect on therapy outcomes. There’s a vast space of bio-active chemicals in foods with both, beneficial and adverse effects, and several recent studies suggest that interactions between these molecules and drugs occur frequently.  More specifically, breast cancer patients taking palbociclib/letrozole should consider limiting their exposure to foods that contain xenoestrogens and maintain a healthy, well-balanced diet. Moreover, we recommend to avoid food supplements rich in phytoestrogens.

Finally, I would like to mention that metabolomics is a unique and powerful tool to comprehensively investigate these complex drug-exposome interactions. Only the technological advances gained during the last decade made it possible to acquire and process the information-rich data sets obtained in this study. What recommendations do you have for future research as a result of this work?

Response: So far we worked in a cell model, this needs to be expanded to animals and ultimately to humans. To do this kind of research we need to develop analytical methods enabling the simultaneous and accurate quantification of multiple xenoestrogens in urine and serum to better understand exposure patterns. Furthermore, it will be important to explore how other xenoestrogens and xenoestrogen mixtures modulate the therapy. Is there anything else you would like to add?

Response:  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. We generally know very little about the interactions of bio-active compounds we are exposed to through our food or the environment with drug treatments, so in this field there are likely many clinically relevant discoveries yet to be made.

No disclosures. Funding for the research came from the Austrian Science Fund (Erwin-Schrödinger fellowship awarded to Benedikt Warth), the George E. Hewitt Foundation for Medical Research and the National Institutes of Health (grants R01 GMH4368 and PO1 A1043376-02S1).


TSRI PR release:



Metabolomics Reveals that Dietary Xenoestrogens Alter Cellular Metabolism Induced by Palbociclib/Letrozole Combination Cancer Therapy

Benedikt Warth,Philipp Raffeiner,Ana Granados,Tao Huan,Mingliang Fang,

Erica M. Forsberg,Paul Benton,Laura Goetz, Caroline H. Johnson,Gary Siuzdak

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