Toward a molecular understanding of human breast cancer: a hypothesis.

A rate limiting step in most metastatic breast cancers is the development of unlimited proliferative potential by mammary epithelial cells. We describe mechanisms by which these cells can attain this state. The two independent mortality mechanisms controlling fibroblast senescence and immortalization (M1 and M2) are also found in human mammary epithelial cells. However, although both p53 and Rb are involved in the M1 mechanism of fibroblast cellular senescence, in human mammary epithelial cells only p53 is involved. The M1/M2 mechanisms may be induced by the gradual loss of telomere ends that occur as normal cells divide. Loss of telomere ends may result in genomic instability and in altered gene expression due to heterochromatin changes in subtelomeric regions. Events which can abrogate p53 functions are described, as is the current state of knowledge about the function of p53. All these factors are included in a molecular model for the onset of breast cancer.