Figure 4.

Conceptual model of benign breast disease (BBD) to breast cancer progression incorporating the contributions of histologic changes in epithelium, stroma, and epithelium-to-stroma proportion (ESP) to breast cancer risk. Increasing ESP is displayed vertically, from bottom to top, to correspond to observed association with increasing risk of subsequent breast cancer development in this study (Table 2). The context-dependent role of the stroma to either inhibit or promote tumor formation in the setting of nonproliferative or proliferative disease (Table 2), respectively, is displayed horizontally. In this conceptual model of BBD to breast cancer progression, we propose that the proportion of the epithelial and stromal components of the breast is in a delicate balance during normal homeostasis. Disruption of this balance, either through uncontrolled epithelial proliferation arising from endogenous and/or exogenous factors, lack of age-related epithelial involution, or via exogeneous and/or endogenous causes of stromal depletion, will manifest as increasing histologic-ESP (Supplementary Table 7, available online). High histologic-ESP may, in turn, represent a feature of the breast microenvironment that is conducive to carcinogenesis.