Senescence and genomic integrity are thought to be important barriers in the development of malignant lesions1. Human fibroblasts undergo a limited number of cell divisions before entering an irreversible arrest, called senescence2. 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 plateau (termed selection or M0; refs 3,4,5), from which proliferative cells emerge to undergo further population doublings (∼20–70), before entering a second growth plateau (previously termed senescence or M1; refs 4,5,6). We find that the first growth plateau exhibits characteristics of senescence but is not an insurmountable barrier to further growth. HMECs emerge from senescence, exhibit eroding telomeric sequences and ultimately enter telomere-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.
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We thank E. H. Blackburn, I. Herskowitz and J. Li for comments, criticism and reading the manuscript. Stimulating discussion and thoughtful critique were provided by Y. Crawford, G. Whitworth, M. Heiman, M. Springer, D. Crawford, P. Hein and J. Anderson. We thank S. Gilbert for assistance with the figures; P. Ortiz for library support; and G. Williams for MCM2 antibodies. This work was supported by NIH and NIH/NASA grants to T.D.T. and a DOE and NIH grant to M.R.S. C.R.H. is supported by a Howard Hughes Pre-doctoral Fellowship.
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Cancer Letters (2019)
Ageing Research Reviews (2019)
Journal of Theoretical Biology (2019)