Quis custodiet ipsos custodies: who watches the watchmen?

Abstract

This Commentary highlights two articles in this issue of the American Journal of Pathology, discussing the implications of stromal expression of caveolin-1 in breast cancer.

Figure 1

Stromal Caveolin-1 (Cav-1) expression predicts breast cancer patient outcome. In this issue of AJP, Sloan et al and Witkiewicz et al show that an absence of staining for the structural protein Cav-1 in the breast tumor microenvironment (reflected by reduced shading of myoepithelial cells, blue, and fibroblasts, green) is predictive of poor clinical outcome for breast cancer patients. Importantly, Cav-1 expression in the tumor epithelium does not correlate with patient outcome.

Figure 2

Three possible scenarios by which Cav-1 loss mediates tumor invasion in the breast tumor microenvironment. Left: Schematic view of a cross-sectioned normal mammary duct. An inner layer of luminal epithelial cells (red) is surrounded basally by myoepithelial cells (blue) and basement membrane (black). Right: Loss of Cav-1 could coincide with or result in 3 distinct scenarios. Scenario 1: Absence of Cav-1 coincides with loss of myoepithelial cells (MEPs). MEPs are more often found in benign breast lesions than in advanced carcinomas. Since Cav-1 is expressed by MEPs, MEP loss would be reflected by an absence of Cav-1 staining. Scenario 2: Loss of Cav-1 mediates loss of MEP function, resulting in invasive ductal carcinoma. Cancer-associated MEPs behave distinctly from normal MEPs, which function as tumor suppressors. Loss of Cav-1 may directly alter the secretion profile of MEPs such that they are unable to regulate architecture, ultimately resulting in tumor invasion. Scenario 3: Loss of Cav-1 induces differentiation of surrounding fibroblasts to a carcinoma-associated fibroblast (CAF) phenotype. Normal breast fibroblasts express Cav-1., Loss of Cav-1 in fibroblasts could directly initiate their transition to CAFs (green), which secrete a variety of factors to promote invasion and possibly inhibit the production of Cav-1 in other cell types (eg, MEPs), thereby further promoting invasion by the means described in Scenario 2.