Regulation of the cell cycle and P13K/AKT/mTOR signaling pathway by phthalates in normal human breast cells

作者：Chen FP, Chien MH, Lee CH · 发表于：Taiwanese journal of obstetrics & gynecology · 年份：2023 · DOI：10.1016/j.tjog.2022.08.020 · 研究领域：Breast Neoplasms、Diethylhexyl Phthalate、Phthalic Acids、Female、Humans、Cell Division、Cyclin A、Dibutyl Phthalate、Proto-Oncogene Proteins c-akt、Signal Transduction、TOR Serine-Threonine Kinases、Phosphatidylinositol 3-Kinases

OBJECTIVE: To investigate the impact of phthalates, including Butyl benzyl phthalate (BBP), di(n-butyl) phthalate (DBP), and di(2-ethylhexyl) phthalate (DEHP), in breast carcinogenesis. MATERIALS AND METHODS: MCF-10A normal breast cells were treated with phthalates (100 nM) and 17β-estradiol (E2, 10 nM), which were co-cultured with fibroblasts from normal mammary tissue adjacent to estrogen receptor positive primary breast cancers. Cell viability was determined using a 3-(4,5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Cell cycles were analyzed using flow cytometry. The proteins involving cell cycles and P13K/AKT/mTOR signaling pathway were then evaluated by Western blot analysis. RESULTS: MCF-10A co-cultured cells treated with E2, BBP, DBP, and DEHP exhibited a significant increase in cell viability using MTT assay. The expressions of P13K, p-AKT, and p-mTOR, as well as PDK1 expression, were significantly higher in MCF-10A cells treated with E2 and phthalates. E2, BBP, DBP, and DEHP significantly increased cell percentages in the S and G2/M phases. The significantly higher expression of cyclin D/CDK4, cyclin E/CDK2, cyclin A/CDK2, cyclin A/CDK1, and cyclin B/CDK1 in MCF-10A co-cultured cells were induced by E2 and these three phthalates. CONCLUSION: These results provide consistent data regarding the potential role of phthalates exposure in the stimulating proliferation of normal breast cells, enhancing cell viability, and driving P13K/AKT/mTOR sig...