Abstract
PurposeMenopause is associated with an increased risk of estrogen receptor-positive (ER +) breast cancer. To characterize the metabolic shifts associated with reduced estrogen bioavailability on breast tissue, metabolomics was performed from ovary-intact and ovariectomized (OVX) female non-human primates (NHP). The effects of exogenous estrogen administration or estrogen receptor blockade (tamoxifen treatment) on menopause-induced metabolic changes were also investigated.MethodsBilateral ovariectomies were performed on female cynomolgus macaques (Macaca fascicularis) to model menopause. OVX NHP were then divided into untreated (n = 13), conjugated equine estrogen (CEE)-treated (n= 13), or tamoxifen-treated (n = 13) subgroups and followed for 3 years. Aged-matched ovary-intact female NHP (n = 12) were used as a premenopausal comparison group. Metabolomics was performed on snap-frozen breast tissue.ResultsChanges in several different metabolic biochemicals were noted, particularly in glucose and fatty acid metabolism. Specifically, glycolytic, Krebs cycle, acylcarnitines, and phospholipid metabolites were elevated in breast tissue from ovary-intact NHP and OVX + CEE in relation to the OVX and OVX + tamoxifen group. In contrast, treatment with CEE and tamoxifen decreased several cholesterol metabolites, compared to the ovary-intact and OVX NHP. These changes were accompanied by elevated bile acid metabolites in the ovary-intact group.ConclusionAlterations in estrogen bioavailability are associated with changes in the mammary tissue metabolome, particularly in glucose and fatty acid metabolism. Changes in these pathways may represent a bioenergetic shift in gland metabolism at menopause that may affect breast cancer risk.
Highlights
Breast cancer is the most common form of cancer in the USA
Pyruvate was significantly elevated in ovary-intact and OVX + conjugated equine estrogens (CEE) non-human primates (NHP) compared to OVX NHP (Fig. 2D). 3-phosphoglycerate levels were elevated in no-OVX, CEE- and TAM-treated NHP compared to OVX NHP (Fig. 2E)
Decreased glucose metabolism in the OVX group suggests that endogenous E2 promotes glycolysis in the mammary tissue
Summary
Breast cancer is the most common form of cancer in the USA. Breast cancer accounts for 30% of all cancer diagnoses, with 281,550 new cases estimated in 2021 [1]. Factors related to estrogen production are linked to an increased breast cancer risk, suggesting a mechanistic association between estrogen signaling and the development of breast carcinogenesis [2,3,4,5]. Late menopause, obesity, or the use of hormone replacement therapies, which all increase lifetime exposure to estrogen, are associated with increased breast cancer risk in both pre-and postmenopausal women. Circulating estrogen and postmenopausal breast cancer risk are linked in numerous studies [9,10,11]. The Endogenous Hormones and Breast Cancer Collaborative Group
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