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).
Highlights
The development of breast cancer is associated with an exposure to increased levels of circulating estrogens e.g., 17β-estradiol (E2), estrone (E1) and other endogenous steroids over a prolonged period of time (Endogenous Hormones Breast Cancer Collaborative Group 2002, 2013; Colditz and Bohlke 2014)
It was shown that modifiable risk factors associated with both increased breast cancer risk (Grosse et al 2009; Colditz and Bohlke 2014; Gaudet et al 2017; Collaborative Group on Hormonal Factors in Breast Cancer 2019; Gram et al 2019) and higher levels of circulating E2 and E1 (Endogenous Hormones Breast Cancer Collaborative Group 2003, 2011, 2013) influenced estrogen levels in human breast glandular and adipose tissues (Pemp et al 2020)
To investigate the relevance of this observation, the influence of intraglandular estrogen levels and breast cancer risk factors on ESR1-mediated cell proliferation and formation of adducts of estrogens with DNA was investigated by multiple linear regression models and metabolic network modeling (Fig. 1)
Summary
The development of breast cancer is associated with an exposure to increased levels of circulating estrogens e.g., 17β-estradiol (E2), estrone (E1) and other endogenous steroids over a prolonged period of time (Endogenous Hormones Breast Cancer Collaborative Group 2002, 2013; Colditz and Bohlke 2014). Estrogen receptor alpha (ESR1)-mediated stimulation of proliferation of the epithelial cells contributes to conversion of DNA damage into mutations (i.e., tumor initiation) as well as tumor promotion and progression (Yager 2015). ESR1-mediated proliferation involves complex intercellular signaling between epithelial and stromal cells (Lanigan et al 2007). The association of intramammary levels of E2 and E1 with the signaling leading to ESR1dependent proliferation in human breast tissues in women without breast cancer is hitherto unexplored
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