Normal human mammary epithelial cells spontaneously escape senescence and acquire genomic changes

Senescence and genomic integrity are thought to be important barriers in th e development of malignant lesions(1). Human fibroblasts undergo a limited number of cell divisions before entering an irreversible arrest, called sen escence(2). Here we show that human mammary epithelial cells (HMECs) do not conform to this paradigm of senescence. In contrast to fibroblasts, HMECs exhibit an initial growth phase that is followed by a transient growth plat eau (termed selection or M0; refs 3-5), from which proliferative cells emer ge to undergo further population doublings (similar to 20-70), before enter ing a second growth plateau (previously termed senescence or M1; refs 4-6). We rnd that the first growth plateau exhibits characteristics of senescenc e but is not an insurmountable barrier to further growth. HMECs emerge from senescence, exhibit eroding telomeric sequences and ultimately enter telom ere-based crisis to generate the types of chromosomal abnormalities seen in the earliest lesions of breast cancer. Growth past senescent barriers may be a pivotal event in the earliest steps of carcinogenesis, providing many genetic changes that predicate oncogenic evolution. The differences between epithelial cells and fibroblasts provide new insights into the mechanistic basis of neoplastic transformation.