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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

Please always quote using this URN: urn:nbn:de:bvb:20-opus-265343
  • 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 estrogenBreast 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).show moreshow less

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Metadaten
Author: Juliane Wunder, Daniela Pemp, Alexander Cecil, Maryam Mahdiani, René Hauptstein, Katja Schmalbach, Leo N. Geppert, Katja Ickstadt, Harald L. Esch, Thomas Dankekar, Leane Lehmann
URN:urn:nbn:de:bvb:20-opus-265343
Document Type:Journal article
Faculties:Fakultät für Biologie / Theodor-Boveri-Institut für Biowissenschaften
Fakultät für Chemie und Pharmazie / Institut für Pharmazie und Lebensmittelchemie
Language:English
Parent Title (English):Archives of Toxicology
ISSN:1432-0738
Year of Completion:2022
Volume:96
Issue:2
Pagenumber:673–687
Source:Archives of Toxicology 2022, 96(2):673–687. DOI: 10.1007/s00204-021-03198-7
DOI:https://doi.org/10.1007/s00204-021-03198-7
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/34921608
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:estrogens; human breast; metabolic network model; multiple linear regression
Release Date:2022/07/25
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International