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A novel targeted approach to delineate a role for estrogen receptor-β in ameliorating murine mammary tumor-associated neuroinflammation

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Abstract

Purpose

Circulating estrogens in breast cancer patients and survivors are often extremely low due to menopause and estrogen-reducing cancer treatments. Simultaneously, circulating inflammatory markers, and inflammatory proteins in brains of rodent tumor models, can be elevated and correlate with debilitating neurological and psychological comorbidities. Because estrogen has anti-inflammatory properties in the brain, we hypothesized that mammary tumor-induced neuroinflammation is driven, in part, by reduced brain estrogen signaling.

Methods

An ovariectomized mouse model of postmenopausal breast cancer utilizing the ERα-positive 67NR mammary tumor cell line was used for these experiments. A novel, orally bioavailable, and brain penetrant ERβ agonist was administered daily via oral gavage. Following treatment, estrogen-responsive genes were measured in brain regions. Central and circulating inflammatory markers were measured via RT-qPCR and a multiplex cytokine array, respectively.

Results

We present novel findings that peripheral mammary tumors alter estrogen signaling genes including receptors and aromatase in the hypothalamus, hippocampus, and frontal cortex. Mammary tumors induced peripheral and central inflammation, however, pharmacological ERβ activation was not sufficient to reduce this inflammation.

Conclusions

Data presented here suggest that compensating for low circulating estrogen with ERβ brain activation is not sufficient to attenuate mammary tumor-induced neuroinflammation, and is therefore not a likely candidate for the treatment of behavioral symptoms in patients. The novel finding that mammary tumors alter estrogen signaling-related genes is a clinically relevant advancement to the understanding of how peripheral tumor biology modulates neurobiology. This is necessary to predict and prevent behavioral comorbidities (e.g., cognitive impairment) prevalent in cancer patients and survivors.

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Data availability

Primary data will be made available upon request. For access to OSU-ERβ-12 please consult Dr. Christopher Coss of The Ohio State University, Comprehensive Cancer Center, Drug Development Institute.

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Acknowledgements

The authors thank Lindsay Strehle, Valerie Burch, Ann Thomas, and Aliza Khuro for their skilled technical assistance, as well as Megan Fleming and Dr. Stacey Meeker for animal husbandry and veterinary support, respectively. We also acknowledge Drs. Christopher Coss and Chad Bennet of The Ohio State University, Comprehensive Cancer Center, Drug Development Institute for their technical help using and quantifying the novel compound.

Author contributions

K.L.G.R. and L.M.P. contributed to the conceptual design of the study. K.L.G.R. and C.V.G. were responsible for data collection and analysis. All authors contributed to data interpretation, paper preparation, and approved the final version of the paper for submission.

Funding

This work was supported by The Ohio State University Comprehensive Cancer Center’s Drug Development Institute (institutional grant, 2019), funds from The Ohio State College of Medicine, and a NIH/NCI fellowship (K.L.G.R.) [T32CA009338].

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Author notes

  1. Kathryn L. G. Russart

    Present address: Minnesota State University Moorhead, Moorhead, MN, USA

  2. These authors contributed equally: Corena V. Grant, Kathryn L. G. Russart

Authors and Affiliations

  1. Institute for Behavioral Medicine Research, The Ohio State University, Columbus, OH, USA

    Corena V. Grant, Kathryn L. G. Russart & Leah M. Pyter

  2. Department of Psychiatry and Behavioral Health, The Ohio State University, Columbus, OH, USA

    Corena V. Grant & Leah M. Pyter

  3. Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

    Kathryn L. G. Russart & Leah M. Pyter

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Correspondence to Leah M. Pyter.

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The data described here are original and have not been previously published. All procedures and experiments were approved by The Ohio state University Institutional Animal Care and Use Committee (IACUC, 2014A00000093, approved 08/04/2020) and carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

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Grant, C.V., Russart, K.L.G. & Pyter, L.M. A novel targeted approach to delineate a role for estrogen receptor-β in ameliorating murine mammary tumor-associated neuroinflammation. Endocrine 75, 949–958 (2022). https://doi.org/10.1007/s12020-021-02931-7

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