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Breast Cancer Research
Published in: Breast Cancer Research 1/2016

Open Access 01-12-2016 | Research Article

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

Authors: Hisani N. Horne, Mark E. Sherman, Ruth M. Pfeiffer, Jonine D. Figueroa, Zeina G. Khodr, Roni T. Falk, Michael Pollak, Deesha A. Patel, Maya M. Palakal, Laura Linville, Daphne Papathomas, Berta Geller, Pamela M. Vacek, Donald L. Weaver, Rachael Chicoine, John Shepherd, Amir Pasha Mahmoudzadeh, Jeff Wang, Bo Fan, Serghei Malkov, Sally Herschorn, Stephen M. Hewitt, Louise A. Brinton, Gretchen L. Gierach

Published in: Breast Cancer Research | Issue 1/2016

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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.
Appendix
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Metadata
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
Authors
Hisani N. Horne
Mark E. Sherman
Ruth M. Pfeiffer
Jonine D. Figueroa
Zeina G. Khodr
Roni T. Falk
Michael Pollak
Deesha A. Patel
Maya M. Palakal
Laura Linville
Daphne Papathomas
Berta Geller
Pamela M. Vacek
Donald L. Weaver
Rachael Chicoine
John Shepherd
Amir Pasha Mahmoudzadeh
Jeff Wang
Bo Fan
Serghei Malkov
Sally Herschorn
Stephen M. Hewitt
Louise A. Brinton
Gretchen L. Gierach
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2016
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-016-0678-4

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