Digital histologic analysis reveals morphometric patterns of age-related involution in breast epithelium and stroma

Sandhu, Rupninder; Chollet‐Hinton, Lynn; Kirk, Erin L.; Midkiff, Bentley R.; Troester, Melissa A.

doi:10.1016/j.humpath.2015.09.031

Cited by 20 publications

(36 citation statements)

References 32 publications

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“…This work extends prior research in this cohort linking decreased TDLU involution to increased risk of developing breast cancer [7, 15]. We note that several groups have developed automated methods to assess TDLU histology and to estimate levels of involution [15, 17, 18, 33, 34] that agree well with visual assessment. Hence, we view visual assessment of involution levels as a temporary approach to advance this area as automated algorithms are developed.…”

Section: Discussionsupporting

confidence: 80%

Standardized measures of lobular involution and subsequent breast cancer risk among women with benign breast disease: a nested case–control study

Figueroa

Pfeiffer

Brinton

et al. 2016

Breast Cancer Res Treat

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Lesser degrees of terminal duct-lobular unit (TDLU) involution predict higher breast cancer risk; however, standardized measures to quantitate levels of TDLU involution have only recently been developed. We assessed whether three standardized measures of TDLU involution, with high intra/inter pathologist reproducibility in normal breast tissue, predict subsequent breast cancer risk among women in the Mayo benign breast disease (BBD) cohort. We performed a masked evaluation of biopsies from 99 women with BBD who subsequently developed breast cancer (cases) after a median of 16.9 years and 145 age-matched controls. We assessed three metrics inversely related to TDLU involution: TDLU count/mm2, median TDLU span (microns, which approximates acini content), and median category of acini counts/TDLU (0–10; 11–20; 21–30; 31–50; >50). Associations with subsequent breast cancer risk for quartiles (or categories of acini counts) of each of these measures were assessed with multivariable conditional logistic regression to estimate odds ratios (ORs) and 95 % confidence intervals (CI). In multivariable models, women in the highest quartile compared to the lowest quartiles of TDLU counts and TDLU span measures were significantly associated with subsequent breast cancer diagnoses; TDLU counts quartile4 versus quartile1, OR = 2.44, 95 %CI 0.96–6.19, p-trend = 0.02; and TDLU spans, quartile4 versus quartile1, OR = 2.83, 95 %CI = 1.13–7.06, p-trend = 0.03. Significant associations with categorical measures of acini counts/TDLU were also observed: compared to women with median category of <10 acini/TDLU, women with >25 acini counts/TDLU were at significantly higher risk, OR = 3.40, 95 %CI 1.03–11.17, p-trend = 0.032. Women with TDLU spans and TDLU count measures above the median were at further increased risk, OR = 3.75 (95 %CI 1.40–10.00, p-trend = 0.008), compared with women below the median for both of these metrics. Similar results were observed for combinatorial metrics of TDLU acini counts/TDLU, and TDLU count. Standardized quantitative measures of TDLU counts and acini counts approximated by TDLU span measures or visually assessed in categories are independently associated with breast cancer risk. Visual assessment of TDLU numbers and acini content, which are highly reproducible between pathologists, could help identify women at high risk for subsequent breast cancer among the million women diagnosed annually with BBD in the US.

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Section: Discussionsupporting

confidence: 80%

Standardized measures of lobular involution and subsequent breast cancer risk among women with benign breast disease: a nested case–control study

Figueroa

Pfeiffer

Brinton

et al. 2016

Breast Cancer Res Treat

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“…Image enhancement (imaging, resizing and white balance correction) was done using Adobe Photoshop (Adobe Photoshop™ Creative Cloud, 2014.0.0, San Jose, CA, USA). Automated quantitative analyses of epithelial nuclear density and epithelial percent area in H&E stained sections were made according to previously published protocols (Sandhu et al 2016). Digital images were uploaded to eSlide Manager™ and visualized with ImageScope™ v 12.2 (Leica Biosystems).…”

Section: Methodsmentioning

confidence: 99%

Mammary Gland Evaluation in Juvenile Toxicity Studies

et al. 2016

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There are currently no reports describing mammary gland development in the Harlan Sprague Dawley (HSD) rat, the current strain of choice for National Toxicology Program (NTP) testing. Our goals were to empower the NTP, contract labs and other researchers in understanding and interpretation of chemical effects in this rat strain. To delineate similarities/differences between the female and male mammary gland, data were compiled starting on embryonic day 15.5 through postnatal day 70. Mammary gland whole mounts, histology sections, and immunohistochemically-stained tissues for estrogen, progesterone and androgen receptors were evaluated in both sexes; qualitative and quantitative differences are highlighted using a comprehensive visual timeline. Research on endocrine disrupting chemicals in animal models has highlighted chemically-induced mammary gland anomalies which may potentially impact human health. In order to investigate these effects within the HSD strain, 2,3,7,8-tetrachlorodibenzo p-dioxin, diethylstilbestrol or vehicle control was gavage dosed on gestation day 15 and 18 to demonstrate delayed, accelerated and control mammary gland growth in offspring, respectively. We provide illustrations of normal and chemically altered mammary gland development in HSD male and female rats to help inform researchers unfamiliar with the tissue and may facilitate enhanced evaluation of both male and female mammary glands in juvenile toxicity studies.

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“…The H&E slides were scanned into high-resolution digital images using the Aperio Scan-Scope XT Slide Scanner at the Translational Pathology Lab (TPL) at UNC. Image analysis was used to segment images and calculate proportions of epithelial, stromal and fat tissue as described in Sandhu et al [41]. Frozen tissue adjacent to the H&E sections were used for DNA extraction.…”

Section: Sample Preparationmentioning

confidence: 99%

Hormone therapy use and breast tissue DNA methylation: analysis of epigenome wide data from the normal breast study

Harlid

Kirk

et al. 2019

Epigenetics

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Hormone therapy (HT) is associated with increased risk of breast cancer, strongly dependent on type, duration, and recency of use. HT use could affect cancer risk by changing breast tissue transcriptional programs. We hypothesize that these changes are preceded by changes in DNA methylation. To explore this hypothesis we used histologically normal-appearing breast tissue from the Normal Breast Study (NBS). DNA methylation β-values were obtained using the Illumina HumanMethylation 450 BeadChips for 90 samples including all NBS-participants who used HT within 5 y before surgery. Data were analyzed using the reference-free cell mixture method. Cancer Genome Atlas (TCGA) mRNA-Seq data were used to assess correlation between DNA methylation and gene expression. We identified 527 CpG sites in 403 genes that were associated with ever using HT at genome wide significance (FDR q < 0.05), of these, 68 sites were also significantly associated with duration of use or recency of use. Twelve sites reached significance in all analyses one of which was cg01382688 in ARHGEF4 (p < 1.2x10 −7). Mutations in ARHGEF4 have been reported in breast tumors, but this is the first report of possible breast cancer-related DNA methylation changes. In addition, 22 genes included more than one significant CpG site and a majority of these sites were significantly correlated with gene expression. Although based on small numbers, these findings support the hypothesis that HT is associated with epigenetic alterations in breast tissue, and identifies genes with altered DNA methylation states which could be linked to breast cancer development.

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Digital histologic analysis reveals morphometric patterns of age-related involution in breast epithelium and stroma

Cited by 20 publications

References 32 publications

Standardized measures of lobular involution and subsequent breast cancer risk among women with benign breast disease: a nested case–control study

Standardized measures of lobular involution and subsequent breast cancer risk among women with benign breast disease: a nested case–control study

Mammary Gland Evaluation in Juvenile Toxicity Studies

Hormone therapy use and breast tissue DNA methylation: analysis of epigenome wide data from the normal breast study

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