Terminal Duct Lobular Unit Involution of the Normal Breast: Implications for Breast Cancer Etiology

Figueroa, Jonine D.; Pfeiffer, Ruth M.; Patel, Deesha A.; Linville, Laura; Brinton, Louise A.; Gierach, Gretchen L.; Yang, Xiaohong R.; Papathomas, Daphne; Visscher, Daniel W.; Mies, Carolyn; Degnim, Amy C.; Anderson, William F.; Hewitt, Stephen M.; Khodr, Zeina G.; Clare, Susan E.; Storniolo, Anna Maria; Sherman, Mark E.

doi:10.1093/jnci/dju286

Cited by 73 publications

(121 citation statements)

References 48 publications

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“…H&E stained tissue sections were digitized at 20× magnification (Aperio ScanScope CS, Vista, CA), and prepared for web-based viewing and annotation with Digital Image Hub software (SlidePath/Leica, Dublin, Ireland) (12). The lasso tool in Digital Image Hub was used to manually outline and measure total tissue area (mm 2 ) per section.…”

Section: Methodsmentioning

confidence: 99%

“…We have previously found quantitative measures that are inversely associated with TDLU involution (i.e., TDLU count, median TDLU span, and median acini count/TDLU) to be significantly related to breast cancer risk factors among women who donated normal breast tissues (12). In a separate study of women undergoing diagnostic breast biopsy, we determined that risk factor associations with quantitative area and volumetric MD measures exhibited some overlap but divergence as well, particularly for BMI (13).…”

Section: Introductionmentioning

confidence: 99%

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Relationship of Terminal Duct Lobular Unit Involution of the Breast with Area and Volume Mammographic Densities

Gierach

Patel

Pfeiffer

et al. 2016

Cancer Prevention Research

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Elevated mammographic density (MD) is an established breast cancer risk factor. Reduced involution of terminal duct lobular units (TDLUs), the histologic source of most breast cancers, has been associated with higher MD and breast cancer risk. We investigated relationships of TDLU involution with area and volumetric MD, measured throughout the breast and surrounding biopsy targets (peri-lesional). Three measures inversely related to TDLU involution (TDLU count/mm2, median TDLU span, median acini count/TDLU) assessed in benign diagnostic biopsies from 348 women, ages 40–65, were related to MD area (quantified with thresholding software) and volume (assessed with a density phantom) by analysis of covariance, stratified by menopausal status and adjusted for confounders. Among premenopausal women, TDLU count was directly associated with percent peri-lesional MD (P-trend=0.03), but not with absolute dense area/volume. Greater TDLU span was associated with elevated percent dense area/volume (P-trend<0.05) and absolute peri-lesional MD (P=0.003). Acini count was directly associated with absolute peri-lesional MD (P=0.02). Greater TDLU involution (all metrics) was associated with increased nondense area/volume (P-trend≤0.04). Among postmenopausal women, TDLU measures were not significantly associated with MD. Among premenopausal women, reduced TDLU involution was associated with higher area and volumetric MD, particularly in peri-lesional parenchyma. Data indicating that TDLU involution and MD are correlated markers of breast cancer risk suggest that associations of MD with breast cancer may partly reflect amounts of at-risk epithelium. If confirmed, these results could suggest a prevention paradigm based on enhancing TDLU involution and monitoring efficacy by assessing MD reduction.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Relationship of Terminal Duct Lobular Unit Involution of the Breast with Area and Volume Mammographic Densities

Gierach

Patel

Pfeiffer

et al. 2016

Cancer Prevention Research

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“…One sample was fixed in 10% buffered formalin, routinely processed to prepare paraffin embedded blocks, sectioned at 5 μm, and stained with hematoxylin and eosin. Digitized images of these sections were used for analysis of percent fat on tissue slide (≤50%, 51-75%, and >75%) and measurements of TDLU involution are described in detail elsewhere (15). …”

Section: Methodsmentioning

confidence: 99%

“…We developed three reproducible TDLU involution measures, based on morphometric TDLU assessment (i.e., TDLU counts, span, and acini counts per TDLU), which are inversely associated with TDLU involution (15). Assessment of these measures among women in the Susan G. Komen Tissue Bank at the Indiana University Simon Cancer center (KTB), a unique resource of normal breast tissue samples, blood samples, and clinical data, found older age, parity, and menopausal status amongst the predominant characteristics associated with TDLU involution.…”

Section: Introductionmentioning

confidence: 99%

Circulating Sex Hormones and Terminal Duct Lobular Unit Involution of the Normal Breast

Khodr

Sherman

Pfeiffer

et al. 2014

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background Terminal duct lobular units (TDLUs) are the predominant source of breast cancers. Lesser degrees of age-related TDLU involution have been associated with increased breast cancer risk, but factors that influence involution are largely unknown. We assessed whether circulating hormones, implicated in breast cancer risk, are associated with levels of TDLU involution using data from the Susan G. Komen Tissue Bank (KTB) at the Indiana University Simon Cancer Center (2009-2011). Methods We evaluated three highly reproducible measures of TDLU involution, using normal breast tissue samples from the KTB (n=390): TDLU counts, median TDLU span, and median acini counts per TDLU. Relative risks (RRs, for continuous measures), odds ratios (ORs, for categorical measures), 95% confidence intervals (CIs), and p-trends were calculated to assess the association between tertiles of estradiol, testosterone, sex hormone-binding globulin (SHBG), progesterone, and prolactin with TDLU measures. All models were stratified by menopausal status and adjusted for confounders. Results Among premenopausal women, higher prolactin levels were associated with higher TDLU counts (RRT3vsT1:1.18, 95% CI: 1.07-1.31; p-trend=0.0005), but higher progesterone was associated with lower TDLU counts (RRT3vsT1: 0.80, 95% CI: 0.72-0.89; p-trend<0.0001). Among postmenopausal women, higher levels of estradiol (RRT3vsT1:1.61, 95% CI: 1.32-1.97; p-trend<0.0001) and testosterone (RRT3vsT1: 1.32, 95% CI: 1.09-1.59; p-trend=0.0043) were associated with higher TDLU counts. Conclusions These data suggest that select hormones may influence breast cancer risk potentially through delaying TDLU involution. Impact Increased understanding of the relationship between circulating markers and TDLU involution may offer new insights into breast carcinogenesis.

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“…TDLUs are the structures of the breast that produce milk and also give rise to breast cancer precursors. TDLUs undergo a range of morphological changes related to puberty, pregnancy, lactation, aging, and menopause,[133, 134] and can also accompany altered molecular histology and a change in mammographic density. Studies have found that, among women with benign breast biopsy, reduced levels of TDLU involution in the surrounding normal breast are associated with breast cancer risk.…”

Section: Pathology and Pathogenesismentioning

confidence: 99%

Proceedings of the second international molecular pathological epidemiology (MPE) meeting

Ogino

Campbell

Nishihara

et al. 2015

Cancer Causes Control

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Disease classification system increasingly incorporates information on pathogenic mechanisms to predict clinical outcomes and response to therapy and intervention. Technological advancements to interrogate omics (genomics, epigenomics, transcriptomics, proteomics, metabolomics, metagenomics, interactomics, etc.) provide widely-open opportunities in population-based research. Molecular pathological epidemiology (MPE) represents integrative science of molecular pathology and epidemiology. This unified paradigm requires multidisciplinary collaboration between pathology, epidemiology, biostatistics, bioinformatics, and computational biology. Integration of these fields enables better understanding of etiologic heterogeneity, disease continuum, causal inference, and the impact of environment, diet, lifestyle, host factors (including genetics and immunity), and their interactions on disease evolution. Hence, the Second International MPE Meeting was held in Boston in December 2014, with aims to: (1) develop conceptual and practical frameworks; (2) cultivate and expand opportunities; (3) address challenges; and (4) initiate the effort of specifying guidelines for MPE. The meeting mainly consisted of presentations of method developments and recent data in various malignant neoplasms and tumors (breast, prostate, ovarian and colorectal cancers, renal cell carcinoma, lymphoma, and leukemia), followed by open discussion sessions on challenges and future plans. In particular, we recognized need for efforts to further develop statistical methodologies. This meeting provided an unprecedented opportunity for interdisciplinary collaboration, consistent with the purposes of the BD2K (Big Data to Knowledge), GAME-ON (Genetic Associations and Mechanisms in Oncology), and Precision Medicine Initiatives of the U.S.A. National Institute of Health. The MPE Meeting Series can help advance transdisciplinary population science, and optimize training and education systems for 21st century medicine and public health.

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Terminal Duct Lobular Unit Involution of the Normal Breast: Implications for Breast Cancer Etiology

Abstract: Morphometric analysis of TDLU involution warrants further evaluation to understand the pathogenesis of breast cancer and assessing its role as a progression marker for women with benign biopsies or as an intermediate endpoint in prevention studies.

Cited by 73 publications

References 48 publications

Relationship of Terminal Duct Lobular Unit Involution of the Breast with Area and Volume Mammographic Densities

Relationship of Terminal Duct Lobular Unit Involution of the Breast with Area and Volume Mammographic Densities

Circulating Sex Hormones and Terminal Duct Lobular Unit Involution of the Normal Breast

Proceedings of the second international molecular pathological epidemiology (MPE) meeting

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