Bad seeds produce bad crops: A single stage-process of breast carcinogenesis

Abstract

It is a commonly held belief that human breast carcinogenesis is a multi-stage-process, and that progression from pre-invasion to invasion is triggered by overproduction of proteolytic enzymes that cause degradation of the basement membrane. These assumptions are hard to reconcile with two critical facts: (1) a subset of normal appearing tissues share a similar immunohistochemical or genetic profile with malignant counterparts and (2) a vast majority of in situ tumors express high levels of proteolytic enzymes, while only 10–30% of untreated in situ tumors progress to invasion. These facts argue that alternative pathways may play more direct roles in tumor progression and invasion in some cases. Loss of the myoepithelial (ME) cell layer is the most distinct sign associated with invasion. Our recent studies revealed that a subset of normal appearing duct clusters harbored a high frequency of focal ME cell layer disruptions (FMCLD). The residual ME cells of these duct clusters had significantly reduced expression of tumor suppressors, elevated rates of apoptosis and infiltration of immunoreactive cells, and the epithelial cell clusters overlying these disruptions had a significantly elevated frequency of tumor-associated phenotypes. Based on these and other findings, we have proposed that these morphologically normal appearing duct clusters are derived from genetically damaged stem cells, and could progress directly to invasion or metastasis through two pathways: (1) the entire ME basal cell layer is gradually degenerated or disappeared, allowing direct physical contact of epithelial cells with stromal and immunoreactive cells, which induce invasive properties without morphological alterations and (2) ER negative cell clusters overlying FMCLD retain the potential for multi-lineage differentiation that continuously proliferate and provide new cells and their own vascular structures for invasion and metastasis.