Estrogens and Progestins Cooperatively Shift Breast Cancer Cell Metabolism

Abstract

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.

Progesterone Receptor–Mediated Regulation of Cellular Glucose and 18F-Fluorodeoxyglucose Uptake in Breast Cancer

“…The authors also demonstrated rapid, nongenomic progestin signaling through the ERK (extracellular signal–regulated kinase)/RSK (ribosomal S6 kinase) pathway resulting in phosphorylation of PFKFB3 protein and increased enzymatic activity as a dual mechanism for progestin activation of glycolysis in breast cancer cells [ 78 ]. A recently published study also showed that progestin treatment shifts metabolism towards glycolysis in T47D cells and a patient-derived cell line, UCD65, which are highly PR-positive [ 79 ], consistent with our findings with FDG uptake.…”

GPD1 inhibits the carcinogenesis of breast cancer through increasing PI3K/AKT-mediated lipid metabolism signaling pathway

“…And the estrogen levels were strongly correlated with survival in breast cancer patients by the TCGA database ( Fig. 5 B) [ [29] , [30] , [31] ]. The survival probability of pre-menopause was higher than post-menopause in GPD1 low/medium expression levels not only, but also in GPD1 high expression levels.…”

Identification of Candidate Genes in Breast Cancer Induced by Estrogen Plus Progestogens Using Bioinformatic Analysis

“…We should also caution that the presence of DEG in this study should not be considered the sole explanation for the different BC incidence in ET and EPT treatments. Ward et al [ 82 ] recently verified the hypothesis that estrogen-progestin combinations had a distinct metabolic phenotype over either hormone alone and might increase glycolysis (E2 effects) and promote lipid storage (progestin effects). These results exhibited that combination hormone treatment facilitated metabolism shifting in the breast cancer cell and had a more metabolically adaptive state for cell survival, which was another potential mechanism for tumor progression during MHT with EPT.…”