Abstract
Understanding intramammary estrogen homeostasis constitutes the basis of understanding the role of lifestyle factors in breast cancer etiology. Thus, the aim of the present study was to identify variables influencing levels of the estrogens present in normal breast glandular and adipose tissues (GLT and ADT, i.e., 17β-estradiol, estrone, estrone-3-sulfate, and 2-methoxy-estrone) by multiple linear regression models. Explanatory variables (exVARs) considered were (a) levels of metabolic precursors as well as levels of transcripts encoding proteins involved in estrogen (biotrans)formation, (b) data on breast cancer risk factors (i.e., body mass index, BMI, intake of estrogen-active drugs, and smoking) collected by questionnaire, and (c) tissue characteristics (i.e., mass percentage of oil, oil%, and lobule type of the GLT). Levels of estrogens in GLT and ADT were influenced by both extramammary production (menopausal status, intake of estrogen-active drugs, and BMI) thus showing that variables known to affect levels of circulating estrogens influence estrogen levels in breast tissues as well for the first time. Moreover, intratissue (biotrans)formation (by aromatase, hydroxysteroid-17beta-dehydrogenase 2, and beta-glucuronidase) influenced intratissue estrogen levels, as well. Distinct differences were observed between the exVARs exhibiting significant influence on (a) levels of specific estrogens and (b) the same dependent variables in GLT and ADT. Since oil% and lobule type of GLT influenced levels of some estrogens, these variables may be included in tissue characterization to prevent sample bias. In conclusion, evidence for the intracrine activity of the human breast supports biotransformation-based strategies for breast cancer prevention. The susceptibility of estrogen homeostasis to systemic and tissue-specific modulation renders both beneficial and adverse effects of further variables associated with lifestyle and the environment possible.
Highlights
Breast cancer is the most common cancer in women worldwide
Modifiable risk factors associated with lifestyle such as obesity, alcohol consumption (Colditz and Bohlke 2014), smoking (Gaudet et al 2017; Jones et al 2017; Gram et al 2019), and intake of estrogen-active drugs (EADs) for oral contraception (Grosse et al 2009) or hormone replacement therapy (Collaborative Group on Hormonal Factors in Breast Cancer 2019) have been associated with both increased breast cancer risk and higher levels of circulating E2 and E1 (Endogenous Hormones Breast Cancer Collaborative Group 2003, 2011, 2013), suggesting that these risk factors act by affecting intramammary levels of E2/E1
The choice of Explanatory variables (exVARs) is discussed in the results section and more detailed information is given in Online Resource 4
Summary
(E1), and other endogenous steroids in pre- and postmenopausal women (Endogenous Hormones Breast Cancer Collaborative Group 2002, 2013) over a prolonged period of time. Based on these associations as well as an abundance of experiments in vitro and in animal models, the current understanding of the molecular etiology of breast cancer hypothesizes biotransformation of E2/E1 within the breast tissue to catechols and subsequent oxidation to mutagenic quinones possibly initiating tumor formation. Modifiable risk factors associated with lifestyle such as (postmenopausal) obesity, alcohol consumption (Colditz and Bohlke 2014), smoking (Gaudet et al 2017; Jones et al 2017; Gram et al 2019), and intake of estrogen-active drugs (EADs) for oral contraception (Grosse et al 2009) or hormone replacement therapy (Collaborative Group on Hormonal Factors in Breast Cancer 2019) have been associated with both increased breast cancer risk and higher levels of circulating E2 and E1 (Endogenous Hormones Breast Cancer Collaborative Group 2003, 2011, 2013), suggesting that these risk factors act by affecting intramammary levels of E2/E1 (biotransformation products)
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