Telomeric DNA induces apoptosis and senescence of human breast carcinoma cells.
BACKGROUND
Cancer is a leading cause of death in Americans. We have identified an inducible cancer avoidance mechanism in cells that reduces mutation rate, reduces and delays carcinogenesis after carcinogen exposure, and induces apoptosis and/or senescence of already transformed cells by simultaneously activating multiple overlapping and redundant DNA damage response pathways.


METHODS
The human breast carcinoma cell line MCF-7, the adriamycin-resistant MCF-7 (Adr/MCF-7) cell line, as well as normal human mammary epithelial (NME) cells were treated with DNA oligonucleotides homologous to the telomere 3' overhang (T-oligos). SCID mice received intravenous injections of MCF-7 cells followed by intravenous administration of T-oligos.


RESULTS
Acting through ataxia telangiectasia mutated (ATM) and its downstream effectors, T-oligos induced apoptosis and senescence of MCF-7 cells but not NME cells, in which these signaling pathways were induced to a far lesser extent. In MCF-7 cells, experimental telomere loop disruption caused identical responses, consistent with the hypothesis that T-oligos act by mimicking telomere overhang exposure. In vivo, T-oligos greatly prolonged survival of SCID mice following intravenous injection of human breast carcinoma cells.


CONCLUSIONS
By inducing DNA damage-like responses in MCF-7 cells, T-oligos provide insight into innate cancer avoidance mechanisms and may offer a novel approach to treatment of breast cancer and other malignancies.
Yaar
Mina
M
Department of Dermatology, Boston University School of Medicine, Albany Street, Boston, MA 02118-2394, USA.
Eller
Mark S
MS
Panova
Izabela
I
Kubera
John
J
Wee
Lee Hng
LH
Cowan
Kenneth H
KH
Gilchrest
Barbara A
BA
D017209:Apoptosis; D001943:Breast Neoplasms / Q000473:pathology*; D016922:Cellular Senescence; D004249:DNA Damage; D005260:Female; D006801:Humans; D009841:Oligonucleotides; D016615:Telomere / Q000235:genetics*; D014407:Tumor Cells, Cultured
D009841:Oligonucleotides