Περίληψη:
Cancer cell characteristics may play a pivotal role in the response to
therapy by activating or deactivating different molecular pathways. In
the present study, we investigated the implication of breast cancer cell
features, such as HER2 and p53 in the activation of telomerase upon
exposure to ionizing radiation. Telomerase is among the most important
cancer biomarkers, conferring to tumor cells unlimited proliferative
capacity, increased survival potential and resistance to several types
of cellular stress. We investigated possible mechanisms regulating
telomerase in six irradiated breast cancer cell lines (MCF-7,
MCF-7/HER2, MDA-MB-231, SK-BR-3, BT-474 and HBL-100) differing in their
HER2, p53 and ER alpha status. hTERT mRNA expression was evaluated by
real-time PCR and telomerase activity by the TRAP assay. HER2, c-myc,
p53 and p21 protein levels were evaluated by Western blotting. Silencing
of hTERT and HER2 was achieved by small interfering RNA technology.
Chromatin immunoprecipitation was used to evaluate H3 histone
acetylation status, as well as myc/mad/max and p53 transcription factors
interaction with the hTERT promoter. Our results showed for the first
time, that only HER2-positive cells, independently of their p53 status,
upregulated hTERT/telomerase, while knockdown of hTERT increased
radio-sensitivity. Knockdown of HER2 also led to increased
radio-sensitivity and downregulation of hTERT/ telomerase. We also
demonstrated that c-myc and mad1 regulate hTERT expression in all
irradiated breast cancer cells. We conclude, for the first time, that
HER2 phenotype upregulates hTERT through c-myc activation and confers
radio-resistance to breast cancer cells.
Συγγραφείς:
Papanikolaou, Vassilis
Iliopoulos, Dimitrios
Dimou, Ioannis and
Dubos, Stephanie
Tsougos, Ioannis
Theodorou, Kyriaki and
Kitsiou-Tzeli, Sofia
Tsezou, Aspasia
