TY - JOUR
T1 - A novel targeted approach to delineate a role for estrogen receptor-β in ameliorating murine mammary tumor-associated neuroinflammation
AU - Grant, Corena V.
AU - Russart, Kathryn L.G.
AU - Pyter, Leah M.
N1 - Funding Information:
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].
Funding Information:
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. 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. 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].
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2022/3
Y1 - 2022/3
N2 - 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.
AB - 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.
KW - Breast cancer
KW - Cytokines
KW - Hippocampus
KW - Hypothalamus–pituitary–gonadal axis
KW - Neuroendocrinology
UR - http://www.scopus.com/inward/record.url?scp=85119472150&partnerID=8YFLogxK
U2 - 10.1007/s12020-021-02931-7
DO - 10.1007/s12020-021-02931-7
M3 - Article
C2 - 34797509
AN - SCOPUS:85119472150
SN - 1355-008X
VL - 75
SP - 949
EP - 958
JO - Endocrine
JF - Endocrine
IS - 3
ER -