Leptin influences estrogen metabolism and increases DNA adduct formation in breast cancer cells

Samia Shouman, Mohamed Wagih, Marwa Kamel

Abstract


Objective: The elevated incidence of obesity has been paralleled with higher risks of breast cancer. High adiposity increases leptinsecretion from adipose tissue, which in turn increases cancer cell proliferation. The interplay between leptin and estrogen is one ofthe mechanisms through which leptin influences breast carcinogenesis. An unbalanced estrogen metabolism increases theformations of catechol estrogen quinones, DNA adducts, and cancer mutations. This study aims to investigate the effect of leptinon some estrogen metabolic enzymes and DNA adduction in breast cancer cells.

Methods: High performance liquid chromatography (HPLC) was performed to analyze the DNA adducts 4-OHE1[E2]-1-N3adenine and 4-OHE1[E2]-1-N7 guanine. Reporter gene assay, real time reverse transcription polymerase chain reaction (real timeRT-PCR), and Western blot were used to assess the expression of estrogen metabolizing genes and enzymes: Cytochrome P-4501B1 (CYP1B1), Nicotinamide adenine dinucleotide phosphate-quinone oxidoreductase1 (NQO1), and Catechol-O-methyltransferase (COMT).

Results: Leptin significantly increased the DNA adducts 4-OHE1[E2]-1-N3 adenine and 4-OHE1[E2]-1-N7 guanine.Furthermore, leptin significantly upregulated CYP1B1 promoter activity and protein expression. The luciferase promoter activitiesof NQO1 and mRNA levels were significantly reduced. Moreover, leptin greatly reduced the reporter activities of the COMT-P1and COMT-P2 promoters and diminished the protein expression of COMT.

Conclusions: Leptin increases DNA adduct levels in breast cancer cells partly by affecting key genes and enzymes involved inestrogen metabolism. Thus, increased focus should be directed toward leptin and its effects on the estrogen metabolic pathway asan effective approach against breast cancer.


Keywords


Breast cancer; leptin; estrogen metabolism; DNA adducts

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