title: Circulating insulin-like growth factor-I, insulin-like growth factor binding protein-3 and terminal duct lobular unit involution of the breast: a cross-sectional study of women with benign breast disease.
abstract: BACKGROUND
  Terminal duct lobular units (TDLUs) are the primary structures from which breast cancers and their precursors arise. Decreased age-related TDLU involution and elevated mammographic density are both correlated and independently associated with increased breast cancer risk, suggesting that these characteristics of breast parenchyma might be linked to a common factor. Given data suggesting that increased circulating levels of insulin-like growth factors (IGFs) factors are related to reduced TDLU involution and increased mammographic density, we assessed these relationships using validated quantitative methods in a cross-sectional study of women with benign breast disease.
  
  
  METHODS
  Serum IGF-I, IGFBP-3 and IGF-I:IGFBP-3 molar ratios were measured in 228 women, ages 40-64, who underwent diagnostic breast biopsies yielding benign diagnoses at University of Vermont affiliated centers. Biopsies were assessed for three separate measures inversely related to TDLU involution: numbers of TDLUs per unit of tissue area ("TDLU count"), median TDLU diameter ("TDLU span"), and number of acini per TDLU ("acini count"). Regression models, stratified by menopausal status and adjusted for potential confounders, were used to assess the associations of TDLU count, median TDLU span and median acini count per TDLU with tertiles of circulating IGFs. Given that mammographic density is associated with both IGF levels and breast cancer risk, we also stratified these associations by mammographic density.
  
  
  RESULTS
  Higher IGF-I levels among postmenopausal women and an elevated IGF-I:IGFBP-3 ratio among all women were associated with higher TDLU counts, a marker of decreased lobular involution (P-trend = 0.009 and <0.0001, respectively); these associations were strongest among women with elevated mammographic density (P-interaction <0.01). Circulating IGF levels were not significantly associated with TDLU span or acini count per TDLU.
  
  
  CONCLUSIONS
  These results suggest that elevated IGF levels may define a sub-group of women with high mammographic density and limited TDLU involution, two markers that have been related to increased breast cancer risk. If confirmed in prospective studies with cancer endpoints, these data may suggest that evaluation of IGF signaling and its downstream effects may have value for risk prediction and suggest strategies for breast cancer chemoprevention through inhibition of the IGF system.
authors.affiliation: Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Rm. 7-E108, Bethesda, MD, 20892-9774, USA. hisani.madison@fda.hhs.gov.|Present Affiliation: Food and Drug Administration, Silver Spring, MD, USA. hisani.madison@fda.hhs.gov.
authors.forename: Hisani N
authors.initials: HN
authors.lastname: Horne
authors.affiliation: Breast and Gynecologic Cancer Research Group, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. shermanm@exchange.nih.gov.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Sherman
authors.affiliation: Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. pfeiffer@mail.nih.gov.
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Pfeiffer
authors.affiliation: Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, Scotland. figueroaj@mail.nih.gov.
authors.forename: Jonine D
authors.initials: JD
authors.lastname: Figueroa
authors.affiliation: Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Rm. 7-E108, Bethesda, MD, 20892-9774, USA. zeina.g.khodr.ctr@mail.mil.
authors.forename: Zeina G
authors.initials: ZG
authors.lastname: Khodr
authors.affiliation: Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Rm. 7-E108, Bethesda, MD, 20892-9774, USA. falkr@exchange.nih.gov.
authors.forename: Roni T
authors.initials: RT
authors.lastname: Falk
authors.affiliation: McGill University, Montreal, Québec, Canada. michael.pollak@mcgill.ca.
authors.forename: Michael
authors.initials: M
authors.lastname: Pollak
authors.affiliation: Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Rm. 7-E108, Bethesda, MD, 20892-9774, USA. deesha84@gmail.com.|Present Affiliation: Northwestern University Medical School, Chicago, IL, USA. deesha84@gmail.com.
authors.forename: Deesha A
authors.initials: DA
authors.lastname: Patel
authors.affiliation: Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Rm. 7-E108, Bethesda, MD, 20892-9774, USA. maya.palakal@nih.gov.
authors.forename: Maya M
authors.initials: MM
authors.lastname: Palakal
authors.affiliation: Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Rm. 7-E108, Bethesda, MD, 20892-9774, USA. lmlinville@gmail.com.
authors.forename: Laura
authors.initials: L
authors.lastname: Linville
authors.affiliation: Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Rm. 7-E108, Bethesda, MD, 20892-9774, USA. dcp448@gmail.com.
authors.forename: Daphne
authors.initials: D
authors.lastname: Papathomas
authors.affiliation: University of Vermont, Burlington, VT, USA. berta.geller@uvm.edu.
authors.forename: Berta
authors.initials: B
authors.lastname: Geller
authors.affiliation: University of Vermont, Burlington, VT, USA. pvacek@zoo.uvm.edu.
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Vacek
authors.affiliation: University of Vermont, Burlington, VT, USA. donald.weaver@uvmhealth.org.
authors.forename: Donald L
authors.initials: DL
authors.lastname: Weaver
authors.affiliation: University of Vermont, Burlington, VT, USA. Rachael.Chicoine@uvm.edu.
authors.forename: Rachael
authors.initials: R
authors.lastname: Chicoine
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA. John.Shepherd@ucsf.edu.
authors.forename: John
authors.initials: J
authors.lastname: Shepherd
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA. AmirPasha.Mahmoudzadeh@ucsf.edu.
authors.forename: Amir Pasha
authors.initials: AP
authors.lastname: Mahmoudzadeh
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA. jeff.wing.wang.walla.walla@gmail.com.|Present Affiliation: Hokkaido University, Graduate School of Medicine, Sapporo, Japan. jeff.wing.wang.walla.walla@gmail.com.
authors.forename: Jeff
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA. BO.FAN@ucsf.edu.
authors.forename: Bo
authors.initials: B
authors.lastname: Fan
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA. Serghei.Malkov@ucsf.edu.
authors.forename: Serghei
authors.initials: S
authors.lastname: Malkov
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA. sally.herschorn@uvmhealth.org.
authors.forename: Sally
authors.initials: S
authors.lastname: Herschorn
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. hewitts@mail.nih.gov.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hewitt
authors.affiliation: Office of the Director, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. brintonl@exchange.nih.gov.
authors.forename: Louise A
authors.initials: LA
authors.lastname: Brinton
authors.affiliation: Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Rm. 7-E108, Bethesda, MD, 20892-9774, USA. gierachg@mail.nih.gov.
authors.forename: Gretchen L
authors.initials: GL
authors.lastname: Gierach
mesh_terms: D000328:Adult; D000368:Aged; D001940:Breast / Q000473:pathology; D000071060:Breast Density; D001941:Breast Diseases / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood / Q000235:genetics*; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism; D042361:Mammary Glands, Human / Q000002:abnormalities; D008327:Mammography; D008875:Middle Aged; D012307:Risk Factors
chemical_list: D018972:Insulin-Like Growth Factor Binding Protein 3; D007334:Insulin-Like Growth Factor I