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

Abstract

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 signaling pathway and cell cycle progression. These findings strongly support the hypothesis that phthalates may play a crucial role in breast tumorigenesis.

• Authors: Fang-Ping Chen, Mei-Hua Chien, Chun-Hui Lee
• Journal: Taiwanese journal of obstetrics & gynecology (Taiwan J Obstet Gynecol) Vol. 62 Issue 3 Pg. 434-439 (May 2023) ISSN: 1875-6263 [Electronic] China (Republic : 1949- )
• PMID: 37188449 (Publication Type: Journal Article)
• Copyright: Copyright © 2023. Published by Elsevier B.V.

Chemical References

• Cyclin A
• Dibutyl Phthalate
• Diethylhexyl Phthalate
• MTOR protein, human
• phthalic acid
• Phthalic Acids
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Phosphatidylinositol 3-Kinases

Topics

• Female
• Humans
• Breast Neoplasms
• Cell Division
• Cyclin A (metabolism)
• Dibutyl Phthalate (pharmacology)
• Diethylhexyl Phthalate (pharmacology)
• Phthalic Acids (toxicity)
• Proto-Oncogene Proteins c-akt
• Signal Transduction
• TOR Serine-Threonine Kinases
• Phosphatidylinositol 3-Kinases (metabolism)