Focal degeneration of aged or injured myoepithelial cells and the resultant auto-immunoreactions are trigger factors for breast tumor invasion

SummaryThe development of breast cancer is believed to be a multi-step process, sequentially progressing from normal to hyperplastic, to in situ, and to invasive stages. The progression from the in situ to invasive stage is believed to be triggered primarily, if not solely, by the overproduction of proteolytic enzymes by cancer cells, which cause degradation of the basement membrane. This theory is consistent with data derived from studies with cell cultures or animal models, while results from recent worldwide clinical trials with a variety of proteolytic enzyme inhibitors have been very disappointing, casting doubt on the validity of the enzyme theory. Based on our recent studies, we propose that breast tumor invasion is triggered by the following mechanisms and events: (1) the predisposition of genetic abnormalities in ME cell replenishment-related genes or other insults results in elevated focal degeneration of ME cells in some individuals; (2) the degradation products of ME cells or diffusible molecules of epithelial cells attract infiltration of immunoreactive cells (IRC) into the affected sites; (3) the direct physical contact between IRC and degenerated ME cells results in the discharge of digestive enzymes from IRC, causing focal disruptions in the ME cell layer; (4) focal disruptions in a given ME cell layer result in a localized loss of tumor suppressors and paracrine inhibitory function, a focal increase of permeability for oxygen, nutrients, and growth factors, and a localized increase of leukocyte infiltration, which facilitate the monoclonal proliferation of tumor progenitors, forming a biologically more aggressive cell cluster overlying the disrupted ME cell layer; (5) the direct physical contact between the newly formed cell cluster and stromal cells stimulates the production of tenascin and other invasion-associated molecules that facilitate tissue remodeling, angiogenesis, and epithelial-mesenchymal transition, providing a favorable micro-environment for proliferation and invasion. Our hypothesis differs from the enzyme theory in the stage of tumor invasion, the cellular origin of invasive lesions, the significance of IRC and stromal cells, and the potential approaches for treatment and prevention. If confirmed, our hypothesis could facilitate the early detection of specific individuals at increased risk to develop invasive breast cancer. More importantly, our hypothesis may facilitate development of novel approaches, including stimulating ME cell growth, neutralizing ME cell degradation products, manipulating the types and extent of IRC infiltration, and controlling the extent of stromal reactions, to combat tumor invasion.