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Vol. 8, Issue 12, 2391-2405, December 1997
and
*Lawrence Berkeley National Laboratory, Berkeley California 94720;
and
Examination of the process of immortal transformation in early
passages of two human mammary epithelial cell (HMEC) lines suggests the
involvement of an epigenetic step. These lines, 184A1 and 184B5, arose
after in vitro exposure of finite lifespan 184 HMEC to a chemical
carcinogen, and both are clonally derived. Although early-passage mass
cultures of 184A1 and 184B5 maintained continuous slow growth, most
individual cells lost proliferative ability. Uniform good growth did
not occur until 20-30 passages after the lines first appeared.
Early-passage cultures expressed little or no telomerase activity and
telomeres continued to shorten with increasing passage. Telomerase
activity was first detected when the telomeres became critically short,
and activity levels gradually increased thereafter. Early-passage
cultures had little or no ability to maintain growth in transforming
growth factor-Geron Corporation, Menlo Park, California 94025
(TGF); however, both mass cultures and clonal
isolates showed a very gradual increase in the number of cells
displaying progressively increased ability to maintain growth in
TGF. A strong correlation between capacity to maintain growth in the
presence of TGF and expression of telomerase activity was observed.
We have used the term "conversion" to describe this process of
gradual acquisition of increased growth capacity in the absence or
presence of TGF and reactivation of telomerase. We speculate that
the development of extremely short telomeres may result in gradual,
epigenetic-based changes in gene expression. Understanding the
underlying mechanisms of HMEC conversion in vitro may provide new
insight into the process of carcinogenic progression in vivo and offer
novel modes for therapeutic intervention.
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