TY  - JOUR
A1  - Wunder, Juliane
A1  - Pemp, Daniela
A1  - Cecil, Alexander
A1  - Mahdiani, Maryam
A1  - Hauptstein, René
A1  - Schmalbach, Katja
A1  - Geppert, Leo N.
A1  - Ickstadt, Katja
A1  - Esch, Harald L.
A1  - Dankekar, Thomas
A1  - Lehmann, Leane
T1  - 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
T2  - Archives of Toxicology
N2  - 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).
KW  - metabolic network model
KW  - estrogens
KW  - human breast
KW  - multiple linear regression
Y1  - 2022
UR  - https://opus.bibliothek.uni-wuerzburg.de/frontdoor/index/index/docId/26534
UR  - https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-265343
SN  - 1432-0738
VL  - 96
IS  - 2
ER  -