TGF‐β superfamily type‐II receptor regulation of telomerase and telomeres in human breast cancer cells

Abstract

Transforming growth factor‐beta (TGF‐β) plays an important role in regulating telomerase activity in cancer cells. Signalling by TGF‐β superfamily ligands is initiated by ligand binding to one of four transmembrane receptor kinases and subsequent phosphorylation of target proteins, resulting in intracellular signalling cascades. Whereas the downstream target protein Smad3 represses the gene coding for telomerase reverse transcriptase (TERT), the roles of the specific receptors of the TGF‐β family in mediating regulation of telomerase activity remain to be established. Many recent studies indicate a key role for the TGF‐β family receptors in cancer cell proliferation, with truncating mutations detected in many cancers ‐ particularly those of breast, colorectal and prostate origin. Such mutations inactivate the kinase ability of these receptors and abolish downstream signalling. This work focuses on the effect of dominant‐negative (DN) type‐II receptors on telomerase and telomeres in breast cancer cells.Human breast cancer MCF‐7 cells were transfected with plasmid constructs expressing truncated type‐II receptors fused to GFP. After approximately 2.5 months stably transfected cells were analysed for telomerase activity, telomere length, cell proliferation and senescence markers. Cells expressing DN‐BMPRII exhibited increased telomerase activity coupled with increased cell proliferation relative to control. Conversely, cells expressing DN‐ACVRIIA/B or DN‐TGFβRII all had decreased telomerase activity, reduced telomere length and an increase in cellular senescence. Taken together these results indicate that BMPRII signalling mediates inhibition of telomerase activity and cell proliferation in MCF7 breast cancer cells, whereas TGFβRII and ACTRIIA/B signalling may be required to sustain telomerase activity and cell proliferation.