Association of reproductive history with breast tissue characteristics and receptor status in the normal breast

Gabrielson, Marike; Chiesa, Flaminia; Behmer, Catharina; Rönnow, Katarina; Czene, Kamila; Hall, Per

doi:10.1007/s10549-018-4768-0

Cited by 18 publications

(37 citation statements)

References 43 publications

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“…We report inverse associations of breastfeeding duration with the proportion of fat tissue. Consistent with our ndings, Gabrielson et al found inverse associations, though only marginally signi cant associations of breastfeeding with the percentage of adipose tissue in the breast (β= -0.55, p = 0.05) [20]. Studies on breast tissue remodeling after lactation in humans are very limited though some studies suggest that the protective effect of breastfeeding on breast cancer risk may be related to the increased cellular proliferation and epithelial exfoliation of breast tissue during lactation with subsequent apoptosis after discontinuation of breastfeeding that could result in elimination of cells which may have DNA damage [4,[31][32][33][34].…”

Section: Discussionsupporting

confidence: 92%

“…We also report, for the rst time, a greater proportion of stroma in nulliparous women and an inverse association of number of children in parous women with proportion of stroma. Consistent with our ndings for epithelium, a recent study by Gabrielson et al of core-biopsy samples of normal breast tissue from 153 cancer-free women found a greater proportion of epithelium in parous as compared to nulliparous women (parous vs. nulliparous β = 0.56, p = 0.07) [20]. In contrast, an earlier study by Gertig et al within NHS, found no associations of parity with proportion of epithelium or stroma.…”

Section: Discussionsupporting

confidence: 89%

“…Compared to our study, this study was small (n = 300) and used a different method of computer-assisted image analysis [21]. Finally, even though neither of the previous studies found associations of parity with the proportion of stroma, Gabrielson et al observed an inverse associations with stromal proliferation [20].…”

Section: Discussioncontrasting

confidence: 60%

“…We did not nd any associations of the length of the time period between menarche and rst birth with any of the tissue types. Gabrielson et al found a marginal positive association of age at rst birth with proportion of epithelium, but the results were not signi cant in the small stratum (n = 55) of premenopausal women [20] and Gertig et al did not nd any associations [21]. Younger age at rst birth may reduce subsequent breast cancer risk by earlier induction of cellular differentiation in the breast [40].…”

Section: Discussionmentioning

confidence: 99%

“…Despite this evidence on the associations of reproductive factors with tissue composition on mammograms, only a few studies have examined these associations using direct measurement of tissue components in normal breast tissue of cancer-free women. Gabrielson et al found positive associations of parity and duration of breastfeeding with epithelial area [20], while an earlier study on associations of reproductive factors with the proportion of epithelium or stroma found no such associations [21].…”

Section: Introductionmentioning

confidence: 99%

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Associations of reproductive breast cancer risk factors with breast tissue composition

Yaghjyan

Austin-Datta

Oh³

et al. 2020

Preprint

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Background We investigated the associations of reproductive factors with percentage of epithelium, stroma, and fat tissue in benign breast biopsy samples. Methods This study included 983 cancer-free women with biopsy-confirmed benign breast disease (BBD) within the Nurses’ Health Study and Nurses’ Health Study II cohorts. Percentage of each tissue type (epithelium stroma, and fat) was measured on whole section images with a deep-learning technique. All tissue measures were log-transformed in all the analyses to improve normality. The data on reproductive variables and other breast cancer risk factors were obtained from biennial questionnaires. Generalized linear regression was used to examine the associations of reproductive factors with percentage of tissue types, while adjusting for known breast cancer risk factors. Results As compared to parous women, nulliparous women had a smaller percentage of epithelium (β= -0.26, 95% confidence interval [CI] -0.41, -0.11) and fat (β= -0.34, 95% CI -0.54, -0.13) and a greater percentage of stroma (β = 0.04, 95% CI 0.01, 0.08). Among parous women, number of children was inversely associated with percentage of stroma (β per child= -0.01 (-0.02, -0.00). Duration of breastfeeding of ≥ 24 months was associated with a reduced proportion of fat (β= -0.30, 95% CI -0.54, -0.06; p-trend = 0.04). In a separate analysis restricted to premenopausal women, older age at first birth was associated with a greater proportion of epithelium and a smaller proportion of stroma. Conclusions Our findings suggest that reproductive factors with a protective effect on breast cancer risk may be associated with a greater proportion of epithelium and a smaller proportion of stroma, potentially suggesting importance of epithelial-stromal interactions. Future studies are warranted to confirm our findings and to elucidate the underlying biological mechanisms.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 89%

Section: Discussioncontrasting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Associations of reproductive breast cancer risk factors with breast tissue composition

Yaghjyan

Austin-Datta

Oh³

et al. 2020

Preprint

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Effects of tamoxifen on normal breast tissue histological composition: Results from a randomised six‐arm placebo‐controlled trial in healthy women

Gabrielson

Hammarström

Bäcklund

et al. 2023

Intl Journal of Cancer

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Tamoxifen prevents recurrence of breast cancer and is suggested for preventive riskreducing therapy. Tamoxifen reduces mammographic density, a proxy for therapy response, but little is known about its effects in remodelling normal breast tissue.Our study, a substudy within the double-blinded dose-determination trial KARISMA, investigated tamoxifen-specific changes in breast tissue composition and histological markers in healthy women. We included 83 healthy women randomised to 6 months daily intake of 20, 10, 5, 2.5, 1 mg of tamoxifen or placebo. The groups were combined to "no dose" (0-1 mg), "low-dose" (2.5-5 mg) or "high-dose" (10-20 mg) of tamoxifen. Ultrasound-guided biopsies were collected before and after tamoxifen exposure. In each biopsy, epithelial, stromal and adipose tissues was quantified, and expression of epithelial and stromal Ki67, oestrogen receptor (ER) and progesterone receptor (PR) analysed. Mammographic density using STRATUS was measured at baseline and end-of-tamoxifen-exposure. We found that different doses of tamoxifen reduced mammographic density and glandular-epithelial area in premenopausal women and associated with reduced epithelium and increased adipose tissue. Highdose tamoxifen also decreased epithelial ER and PR expressions in premenopausal women. Premenopausal women with the greatest reduction in proliferation also had the greatest epithelial reduction. In postmenopausal women, high-dose tamoxifen decreased the epithelial area with no measurable density decrease. Tamoxifen at both low and high doses influences breast tissue composition and expression of histological markers in the normal breast. Our findings connect epithelial proliferation with tissue remodelling in premenopausal women and provide novel insights to understanding biological mechanisms of primary prevention with tamoxifen.

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Baseline breast tissue characteristics determine the effect of tamoxifen on mammographic density change

Gabrielson,

Hammarström,

Bergqvist

et al. 2024

Intl Journal of Cancer

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Tamoxifen prevents recurrence of breast cancer and is also approved for preventive, risk‐reducing, therapy. Tamoxifen alters the breast tissue composition and decreases the mammographic density. We aimed to test if baseline breast tissue composition influences tamoxifen‐associated density change. This biopsy‐based study included 83 participants randomised to 6 months daily intake of placebo, 20, 10, 5, 2.5, or 1 mg tamoxifen. The study is nested within the double‐blinded tamoxifen dose‐determination trial Karolinska Mammography Project for Risk Prediction of Breast Cancer Intervention (KARISMA) Study. Ultrasound‐guided core‐needle breast biopsies were collected at baseline before starting treatment. Biopsies were quantified for epithelial, stromal, and adipose distributions, and epithelial and stromal expression of proliferation marker Ki67, oestrogen receptor (ER) and progesterone receptor (PR). Mammographic density was measured using STRATUS. We found that greater mammographic density at baseline was positively associated with stromal area and inversely associated with adipose area and stromal expression of ER. Premenopausal women had greater mammographic density and epithelial tissue, and expressed more epithelial Ki67, PR, and stromal PR, compared to postmenopausal women. In women treated with tamoxifen (1–20 mg), greater density decrease was associated with higher baseline density, epithelial Ki67, and stromal PR. Women who responded to tamoxifen with a density decrease had on average 17% higher baseline density and a 2.2‐fold higher PR expression compared to non‐responders. Our results indicate that features in the normal breast tissue before tamoxifen exposure influences the tamoxifen‐associated density decrease, and that the age‐associated difference in density change may be related to age‐dependant differences in expression of Ki67 and PR.

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Association of reproductive history with breast tissue characteristics and receptor status in the normal breast

Cited by 18 publications

References 43 publications

Associations of reproductive breast cancer risk factors with breast tissue composition

Associations of reproductive breast cancer risk factors with breast tissue composition

Effects of tamoxifen on normal breast tissue histological composition: Results from a randomised six‐arm placebo‐controlled trial in healthy women

Baseline breast tissue characteristics determine the effect of tamoxifen on mammographic density change

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