Transcript expression and genetic variability analysis of caspases in breast carcinomas suggests CASP9 as the most interesting target.
BACKGROUND
Apoptosis plays a critical role in cancer cell survival and tumor development. We provide a hypothesis-generating screen for further research by exploring the expression profile and genetic variability of caspases (2, 3, 7, 8, 9, and 10) in breast carcinoma patients. This study addressed isoform-specific caspase transcript expression and genetic variability in regulatory sequences of caspases 2 and 9.


METHODS
Gene expression profiling was performed by quantitative real-time PCR in tumor and paired non-malignant tissues of two independent groups of patients. Genetic variability was determined by high resolution melting, allelic discrimination, and sequencing analysis in tumor and peripheral blood lymphocyte DNA of the patients.


RESULTS
CASP3 A+B and S isoforms were over-expressed in tumors of both patient groups. The CASP9 transcript was down-regulated in tumors of both groups of patients and significantly associated with expression of hormonal receptors and with the presence of rs4645978-rs2020903-rs4646034 haplotype in the CASP9 gene. Patients with a low intratumoral CASP9A/B isoform expression ratio (predicted to shift equilibrium towards anti-apoptotic isoform) subsequently treated with adjuvant chemotherapy had a significantly shorter disease-free survival than those with the high ratio (p=0.04). Inheritance of CC genotype of rs2020903 in CASP9 was associated with progesterone receptor expression in tumors (p=0.003).


CONCLUSIONS
Genetic variability in CASP9 and expression of its splicing variants present targets for further study.
Veronika
V
Brynychova
Viktor
V
Hlavac
Marie
M
Ehrlichova
Radka
R
Vaclavikova
Vlasta
V
Nemcova-Furstova
Vaclav
V
Pecha
Marketa
M
Trnkova
Marcela
M
Mrhalova
Roman
R
Kodet
David
D
Vrana
Jiri
J
Gatek
Marie
M
Bendova
Zdenka
Z
Vernerova
Jan
J
Kovar
Pavel
P
Soucek
D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics*; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D014158:Transcription, Genetic
D053453:Caspase 9; D020169:Caspases