Abstract
BackgroundOur 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.MethodsWe 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.ResultsExtensive 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.ConclusionsThese 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.
Highlights
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 PMD decreases with increasing age, breast cancer incidence increases
We summarize evidence that PMD reflects the relative quantities of epithelium, stroma, and fat in the breast, and we use a two-stage model of carcinogenesis as a framework to examine how the known biological properties of these tissues may influence the transition of normal breast epithelial cells to malignant cells [17]
A reduced risk of breast cancer associated with the nondense area of the mammogram has been shown in a meta-analysis by Pettersson et al [3]. The mechanism underlying this protection is currently uncertain, but as shown in Fig. 2, breasts with low PMD are associated with fewer cells and less extensive collagen, tissue components whose biological properties we show are associated with radiologically dense breast tissue and that may contribute to carcinogenesis in the breast
Summary
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 PMD decreases with increasing age, breast cancer incidence increases. Percent mammographic density (PMD) is one of the strongest known risk factors for breast cancer [1]. PMD, illustrated in Additional file 1: Figure S1a, refers to the area of white. Boyd et al Breast Cancer Research (2018) 20:17 associated with an increased risk of lesions that are thought to be nonobligate precursors of breast cancer [8]. Average PMD in the population decreases with increasing age [5]. A cross-sectional study of 11,000 women in 22 countries showed that average PMD declined with increasing age. Longitudinal data within individuals has shown average reductions in PMD of from 5% [10] to 8% [11] respectively over 10 to 5 years
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