Changed lineage composition is an early event in breast carcinogenesis

Abstract

The epithelium compartment of the human breast is made up of a branching ductal-lobular system, which is lined by a single layer of luminal epithelial cells surrounded by contractile myoepithelial cells. The coordinated development of these two cell types, and maintenance of their relative proportions, is fundamentally important for normal breast morphogenesis. Changes in cell type composition is one of the hallmark features of breast cancer progression, and the vast majority of breast tumors are comprised of luminal cells only, with a complete absence of myoepithelial cells. Despite this striking alteration in relative proportions of luminal and myoepithelial cells in invasive breast cancers compared with normal breast tissue, the steps in this dramatic change in cellular composition remain poorly characterised, nor is it known whether loss of myoepithelial cells is an early event in carcinogenesis. In a panel of breast tissues, we quantitated the proportion of luminal cells relative to the surrounding myoepithelial cell layer in a panel of normal and pre-invasive breast tissue samples, including lesions with proliferative disease without atypia (PDWA), columnar cell lesions (CCL), atypical ductal hyperplasia (ADH), and DCIS, and correlated these findings with proliferation in the same lesions. The study findings showed that changes in lineage composition correlate with increased proliferation, and are one of the earliest events in breast carcinogenesis. Therefore not only are myoepithelial cells important in distinguishing between invasive and non-invasive tumors, their relative proportion compared with luminal cell numbers may provide a new potential indicator of which premalignant lesions are at higher risk of progression to invasive disease.