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- Title
Estrogens and Progestins Cooperatively Shift Breast Cancer Cell Metabolism.
- Authors
Ward, Ashley V.; Matthews, Shawna B.; Fettig, Lynsey M.; Riley, Duncan; Finlay-Schultz, Jessica; Paul, Kiran V.; Jackman, Matthew; Kabos, Peter; MacLean, Paul S.; Sartorius, Carol A.
- Abstract
Simple Summary: Breast cancers are largely controlled by hormones, expressing abundant receptors for estrogen (ER) and progesterone (PR). Reprogramming of energy metabolism is a common feature of tumors, yet how estrogen and progestins (synthetic progesterone drugs) control breast cancer cell metabolism, particularly in combination, is understudied. Here we evaluated the impact of estrogens and progestins, alone or together, on breast cancer cell metabolism. Our results show that hormones significantly impact metabolism, especially in combination. Estrogens tend to target tumor-promoting genes that alter glucose metabolism while progestins target fat storage. Combined hormone treatment increases both glucose metabolism and fat storage, features advantageous for tumor progression. These results may explain, in part, why estrogen-progestin combinations increase breast cancer incidence in post-menopausal women. Targeting hormone-regulated metabolism is a potential novel therapeutic strategy for ER+PR+ breast cancer. Metabolic reprogramming remains largely understudied in relation to hormones in estrogen receptor (ER) and progesterone receptor (PR) positive breast cancer. In this study, we investigated how estrogens, progestins, or the combination, impact metabolism in three ER and PR positive breast cancer cell lines. We measured metabolites in the treated cells using ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS). Top metabolic processes upregulated with each treatment involved glucose metabolism, including Warburg effect/glycolysis, gluconeogenesis, and the pentose phosphate pathway. RNA-sequencing and pathway analysis on two of the cell lines treated with the same hormones, found estrogens target oncogenes, such as MYC and PI3K/AKT/mTOR that control tumor metabolism, while progestins increased genes associated with fatty acid metabolism, and the estrogen/progestin combination additionally increased glycolysis. Phenotypic analysis of cell energy metabolism found that glycolysis was the primary hormonal target, particularly for the progestin and estrogen-progestin combination. Transmission electron microscopy found that, compared to vehicle, estrogens elongated mitochondria, which was reversed by co-treatment with progestins. Progestins promoted lipid storage both alone and in combination with estrogen. These findings highlight the shift in breast cancer cell metabolism to a more glycolytic and lipogenic phenotype in response to combination hormone treatment, which may contribute to a more metabolically adaptive state for cell survival.
- Subjects
BREAST tumor prevention; LIQUID chromatography; ESTROGEN; METABOLISM; ANTINEOPLASTIC agents; MASS spectrometry; CELL lines; PROGESTATIONAL hormones; METABOLITES; GLYCOLYSIS; PHARMACODYNAMICS
- Publication
Cancers, 2022, Vol 14, Issue 7, p1776
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers14071776