Expression of the telomerase catalytic subunit, hTERT, induces resistance to transforming growth factor beta growth inhibition in p16INK4A(-) human mammary epithelial cells.
Failures to arrest growth in response to senescence or transforming growth factor beta (TGF-beta) are key derangements associated with carcinoma progression. We report that activation of telomerase activity may overcome both inhibitory pathways. Ectopic expression of the human telomerase catalytic subunit, hTERT, in cultured human mammary epithelial cells (HMEC) lacking both telomerase activity and p16(INK4A) resulted in gaining the ability to maintain indefinite growth in the absence and presence of TGF-beta. The ability to maintain growth in TGF-beta was independent of telomere length and required catalytically active telomerase capable of telomere maintenance in vivo. The capacity of ectopic hTERT to induce TGF-beta resistance may explain our previously described gain of TGF-beta resistance after reactivation of endogenous telomerase activity in rare carcinogen-treated HMEC. In those HMEC that overcame senescence, both telomerase activity and TGF-beta resistance were acquired gradually during a process we have termed conversion. This effect of hTERT may model a key change occurring during in vivo human breast carcinogenesis.
Stampfer
M R
MR
Lawrence Berkeley National Laboratory, Life Sciences Division, Berkeley, CA 94720, USA. mrstampfer@lbl.gov
Garbe
J
J
Levine
G
G
Lichtsteiner
S
S
Vasserot
A P
AP
Yaswen
P
P
D015153:Blotting, Western; D001940:Breast / Q000166:cytology / Q000187:drug effects*; D020134:Catalytic Domain; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D004268:DNA-Binding Proteins; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D012313:RNA; D019098:Telomerase / Q000737:chemistry / Q000378:metabolism*; D016615:Telomere; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D016212:Transforming Growth Factor beta; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase