Influence of breast cancer risk factors on proliferation and DNA damage in human breast glandular tissues: role of intracellular estrogen levels, oxidative stress and estrogen biotransformation

Abstract

Breast cancer etiology is associated with both proliferation and DNA damage induced by estrogens. Breast cancer risk factors (BCRF) such as body mass index (BMI), smoking, and intake of estrogen-active drugs were recently shown to influence intratissue estrogen levels. Thus, the aim of the present study was to investigate the influence of BCRF on estrogen-induced proliferation and DNA damage in 41 well-characterized breast glandular tissues derived from women without breast cancer. Influence of intramammary estrogen levels and BCRF on estrogen receptor (ESR) activation, ESR-related proliferation (indicated by levels of marker transcripts), oxidative stress (indicated by levels of GCLC transcript and oxidative derivatives of cholesterol), and levels of transcripts encoding enzymes involved in estrogen biotransformation was identified by multiple linear regression models. Metabolic fluxes to adducts of estrogens with DNA (E-DNA) were assessed by a metabolic network model (MNM) which was validated by comparison of calculated fluxes with data on methoxylated and glucuronidated estrogens determined by GC– and UHPLC–MS/MS. Intratissue estrogen levels significantly influenced ESR activation and fluxes to E-DNA within the MNM. Likewise, all BCRF directly and/or indirectly influenced ESR activation, proliferation, and key flux constraints influencing E-DNA (i.e., levels of estrogens, CYP1B1, SULT1A1, SULT1A2, and GSTP1). However, no unambiguous total effect of BCRF on proliferation became apparent. Furthermore, BMI was the only BCRF to indeed influence fluxes to E-DNA (via congruent adverse influence on levels of estrogens, CYP1B1 and SULT1A2).

Antidiabetic effects of Brugmansia aurea leaf extract by modulating the glucose levels, insulin resistance, and oxidative stress mechanism

“…The research presented in this article aimed to identify and report the potential antidiabetic effects of specie B. aurea by reducing insulin resistance in animals with the disease. Previous studies reported the anti-inflammatory ( 14 , 17 ) and anticholinergic activities ( 18 ) of this plant. However, no studies are available on its antidiabetic activity.…”

A coding variant in SULT1A2 gene: association with obesity and dyslipidemia in southern Chinese adults

“…Recently, another research showed BMI is the only breast cancer risk factor that affect metabolic uxes to adducts of estrogens with DNA (via congruent adverse in uence on levels of estrogens, CYP1B1 and SULT1A2) [23]. These results suggest that SULT1A2 may be involved in the regulation of body weight and energy balance by regulating steroid metabolism [24].…”