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Breast Cancer Research
Published in: Breast Cancer Research 1/2018

Open Access 01-12-2018 | Research Article

The origins of breast cancer associated with mammographic density: a testable biological hypothesis

Authors: Norman Boyd, Hal Berman, Jie Zhu, Lisa J. Martin, Martin J. Yaffe, Sofia Chavez, Greg Stanisz, Greg Hislop, Anna M. Chiarelli, Salomon Minkin, Andrew D. Paterson

Published in: Breast Cancer Research | Issue 1/2018

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Abstract

Background

Our purpose is to develop a testable biological hypothesis to explain the known increased risk of breast cancer associated with extensive percent mammographic density (PMD), and to reconcile the apparent paradox that although PMD decreases with increasing age, breast cancer incidence increases.

Methods

We used the Moolgavkar model of carcinogenesis as a framework to examine the known biological properties of the breast tissue components associated with PMD that includes epithelium and stroma, in relation to the development of breast cancer. In this model, normal epithelial cells undergo a mutation to become intermediate cells, which, after further mutation, become malignant cells. A clone of such cells grows to become a tumor. The model also incorporates changes with age in the number of susceptible epithelial cells associated with menarche, parity, and menopause. We used measurements of the radiological properties of breast tissue in 4454 healthy subjects aged from 15 to 80+ years to estimate cumulative exposure to PMD (CBD) in the population, and we examined the association of CBD with the age-incidence curve of breast cancer in the population.

Results

Extensive PMD is associated with a greater number of breast epithelial cells, lobules, and fibroblasts, and greater amounts of collagen and extracellular matrix. The known biological properties of these tissue components may, singly or in combination, promote the acquisition of mutations by breast epithelial cells specified by the Moolgavkar model, and the subsequent growth of a clone of malignant cells to form a tumor. We also show that estimated CBD in the population from ages 15 to 80+ years is closely associated with the age-incidence curve of breast cancer in the population.

Conclusions

These findings are consistent with the hypothesis that the biological properties of the breast tissue components associated with PMD increase the probability of the transition of normal epithelium to malignant cells, and that the accumulation of mutations with CBD may influence the age-incidence curve of breast cancer. This hypothesis gives rise to several testable predictions.
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Metadata
Title
The origins of breast cancer associated with mammographic density: a testable biological hypothesis
Authors
Norman Boyd
Hal Berman
Jie Zhu
Lisa J. Martin
Martin J. Yaffe
Sofia Chavez
Greg Stanisz
Greg Hislop
Anna M. Chiarelli
Salomon Minkin
Andrew D. Paterson
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2018
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-018-0941-y

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