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

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.

Keywords: Breast cancer; Carcinogenesis; Mammographic density; Two-stage model.

Fig. 1

Two-stage model of carcinogenesis of Moolgavkar et al. [17]. In this model, normal stem cells, with a birth rate (α₁) and rate of death (β₁), can be transformed into cells of an intermediate form at a stochastic event rate (μ₁) (the first mutation rate). These intermediate cells can divide into two further intermediate cells at a stochastic rate (α₂), then die or differentiate at rate β₂. In addition, intermediate cells can divide into one intermediate and one transformed (malignant) cell with a second stochastic event rate (μ₂). The malignant cells are assumed to develop into a tumor after a deterministic lag time

Fig. 2

Breast tissue components associated with percent mammographic density (PMD). PMD was assessed in the BioVision (Faxitron Bioptics) image of the enucleated breast from which the section had been taken (a) [Li T, et al. Cancer Epidemiol Biomarkers Prev. 2005;14(2):343–9]. We used quantitative microscopy in randomly selected areas of the tissue section (b) to measure the total, epithelial, and nonepithelial nuclear areas (H&E stain in c) as an index of the number of cells (outlined in green in d), the area of collagen (H&E stain in f and Masson’s trichrome in g), and the glandular area. PMD was associated inversely with age, and, after age adjustment, positively with the nuclear area (e) of epithelial and nonepithelial cells, glandular area, and the area of collagen (h). Box plots in e and h show the associations of total nuclear area (e) and collagen (h) with PMD. The median values are shown as horizontal lines, and the boxes show the 25th and 75th percentiles of the distributions. Age, parity, and menopausal status were also associated with variations in one or more of these tissue components. Similar associations of PMD with these breast tissue components have been found in prophylactic mastectomies [13]. Original magnification ×10 (c, d, f, and g)

Fig. 3

Proposed model of the two-stage model of carcinogenesis with risk of breast cancer in percent mammographic density. (The third column represents effects on the growth of a clone of malignant cells.) CAF Cancer-associated fibroblast, ECM Extracellular matrix, HGF Hepatocyte growth factor, IGF-1 Insulin-like growth factor 1, MMP-3 Matrix metalloproteinase 3, TGF-β Transforming growth factor-β

Fig. 4

Cumulative breast density: observed and predicted breast cancer incidence. Left: Breast density according to age. Values derived from mammogram in open circles; values from calibrated measures derived from magnetic resonance in closed circles. Right: Log breast cancer incidence in closed circles, log cumulative breast density in open circles. Incidence data for age-specific incidence of invasive breast cancer for Canada were obtained from Curado MP et al. Cancer incidence in five continents. Vol. IX. IARC Scientific Publication no. 160. Lyon, France: IARC Press; 2007