Circulating Growth and Sex Hormone Levels and Breast Tissue Composition in Young Nulliparous Women

Denholm, Rachel; Stavola, Bianca L De; Hipwell, John H.; Doran, Simon J.; Holly, Jeff M.P.; Folkerd, Elizabeth; Dowsett, Mitch; Leach, Martin O.; Hawkes, David J.; dos‐Santos‐Silva, Isabel

doi:10.1158/1055-9965.epi-18-0036

Cited by 4 publications

(3 citation statements)

References 42 publications

(49 reference statements)

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“…In contrast, oestrone sulphate was somewhat more strongly associated with MD (+ 1.4 cm 2 ) by linear models, but women in the top tertile of oestrone sulphate had only 9% more MD than women in the lowest tertile. Our findings, supported by previous studies [10,37], suggest a more complex association between hormones and breast tissue composition and provide information about the relationship between these risk factors. The non-linear relationship between plasma hormones and MD may also in part explain the lack of association or discrepancy in results between studies.…”

Section: Discussionsupporting

confidence: 90%

Hormonal determinants of mammographic density and density change

et al. 2020

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Background: Mammographic density (MD) is a strong risk factor for breast cancer. We examined how endogenous plasma hormones are associated with average MD area (cm 2) and annual MD change (cm 2 /year). Methods: This study within the prospective KARMA cohort included analyses of plasma hormones of 1040 women. Hormones from the progestogen (n = 3), androgen (n = 7), oestrogen (n = 2) and corticoid (n = 5) pathways were analysed by ultra-performance supercritical fluid chromatography-tandem mass spectrometry (UPSFC-MS/MS), as well as peptide hormones and proteins (n = 2). MD was measured as a dense area using the STRATUS method (mean over the left and right breasts) and mean annual MD change over time. Results: Greater baseline mean MD was associated with overall higher concentrations of progesterone (average + 1.29 cm 2 per doubling of hormone concentration), 17OH-progesterone (+ 1.09 cm 2), oesterone sulphate (+ 1.42 cm 2), prolactin (+ 2.11 cm 2) and SHBG (+ 4.18 cm 2), and inversely associated with 11-deoxycortisol (− 1.33 cm 2). The association between MD and progesterone was confined to the premenopausal women only. The overall annual MD change was − 0.8 cm 2. Hormones from the androgen pathway were statistically significantly associated with MD change. The annual MD change was − 0.96 cm 2 and − 1.16 cm 2 lesser, for women in the highest quartile concentrations of testosterone and free testosterone, respectively, compared to those with the lowest concentrations. Conclusions: Our results suggest that, whereas hormones from the progestogen, oestrogen and corticoid pathways drive baseline MD, MD change over time is mainly driven by androgens. This study emphasises the complexity of risk factors for breast cancer and their mechanisms of action.

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Section: Discussionsupporting

confidence: 90%

Hormonal determinants of mammographic density and density change

et al. 2020

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“…Early menarche, elevated IGF-1 serum levels, increased breast density, and accelerated breast growth during adolescence are well-known risk factors of BC [353][354][355][356][357][358][359]. The intake of sugar-based milk drinks (>125 g/day) increased fibroglandular volume in girls [360].…”

Section: Breast Cancermentioning

confidence: 99%

Lifetime Impact of Cow’s Milk on Overactivation of mTORC1: From Fetal to Childhood Overgrowth, Acne, Diabetes, Cancers, and Neurodegeneration

Melnik

2021

Biomolecules

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The consumption of cow’s milk is a part of the basic nutritional habits of Western industrialized countries. Recent epidemiological studies associate the intake of cow’s milk with an increased risk of diseases, which are associated with overactivated mechanistic target of rapamycin complex 1 (mTORC1) signaling. This review presents current epidemiological and translational evidence linking milk consumption to the regulation of mTORC1, the master-switch for eukaryotic cell growth. Epidemiological studies confirm a correlation between cow’s milk consumption and birthweight, body mass index, onset of menarche, linear growth during childhood, acne vulgaris, type 2 diabetes mellitus, prostate cancer, breast cancer, hepatocellular carcinoma, diffuse large B-cell lymphoma, neurodegenerative diseases, and all-cause mortality. Thus, long-term persistent consumption of cow’s milk increases the risk of mTORC1-driven diseases of civilization. Milk is a highly conserved, lactation genome-controlled signaling system that functions as a maternal-neonatal relay for optimized species-specific activation of mTORC1, the nexus for regulation of eukaryotic cell growth, and control of autophagy. A deeper understanding of milk´s impact on mTORC1 signaling is of critical importance for the prevention of common diseases of civilization.

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“…To date, exploration of androgenic effects on MD have mainly focused on serum androgens; as yet no prospective randomised trial to study MD reduction with androgenic treatment in women has been performed. Relationships between MD and levels of different types of circulating androgens, including testosterone (total and free), androstenedione, dehydroepiandrosterone (DHEA) and DHEA sulphate (DHEAS) have been widely studied, but the results are conflicting and potentially confounded by conversion of circulating androgens to oestrogens [1,5,16,38,41]. Thus, the direct effect of androgen on MD is still unclear.…”

Section: Introductionmentioning

confidence: 99%

Portable NMR for the investigation of models of mammographic density ex vivo: Androgens antagonise the promotional effect of oestrogen

Huang,

Reye,

Momot

et al. 2023

BSI

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Background: Increased mammographic density (MD) is a strong and independent risk factor for breast cancer. Lifetime oestrogenic exposure is associated with increased MD, however androgenic effects on MD have not been widely investigated. Methods: We studied the effect of 17 β-oestradiol (E2) alone or in combination with an androgen receptor (AR) agonist ( 5 α-dihydrotestosterone [DHT]) or a selective AR modulator (Enobosarm), in modulating MD as measured via single-sided Portable NMR in a patient-derived explant (PDE) model of normal human mammary tissue. Results: We observed an upward trend in explants treated with E2 alone in 3/6 cases, an effect which appeared to be somewhat influenced by menopausal status. Co-treatment of E2 with the AR agonists DHT or Enobosarm however effected a downward trend in regards to MD. E2 significantly upregulated the ER regulated genes (ERGs) CELSR2 and AR, and the AR regulated genes SEC14L2 and GRPC5A, whereas E2 in combination with AR agonist Enobosarm downregulated ERGs SERPINA3, ATP6V1B1, TFF1 and PR regulated gene RANK. Only GREB1 and CLIC6 were upregulated by E2 and downregulated by the combination of E2 with Enobosarm. DHT + E2 exhibited no significant difference in expression of ER, AR or PR genes examined, compared with the effect of E2 alone. A negative trend was observed between ER protein levels and MD increase in PDEs. Since ER protein gets degraded upon hormone activation, this observation supports active ER signalling in the promotion of MD. Conclusions: Collectively, these findings supports the utility of single-sided Portable NMR for the measurement of MD in explanted human mammary tissue to detect MD change in response to exogenous hormone treatments. A mechanism through which activation of AR may reduce MD as a potential mechanism for reducing breast cancer risk associated to high MD is discussed.

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Circulating Growth and Sex Hormone Levels and Breast Tissue Composition in Young Nulliparous Women

Abstract: The well-established associations of childhood growth and development with breast cancer risk may be partly mediated by the role of endogenous hormones on breast tissue composition.

Cited by 4 publications

References 42 publications

Hormonal determinants of mammographic density and density change

Hormonal determinants of mammographic density and density change

Lifetime Impact of Cow’s Milk on Overactivation of mTORC1: From Fetal to Childhood Overgrowth, Acne, Diabetes, Cancers, and Neurodegeneration

Portable NMR for the investigation of models of mammographic density ex vivo: Androgens antagonise the promotional effect of oestrogen

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