BRCA1-defective breast tumors are characterized by basal-like molecular phenotype. HCC1937 is a BRCA1-defective breast cancer cell line which discloses higher sensitivity to cisplatinum (CDDP) as compared to the BRCA1 full length cDNA transfected clone HCC1937/wtBRCA1. To study the molecular bases of BRCA1-related differential sensitivity to the drug, we analyzed the whole gene expression profile of HCC1937 and HCC1937/wtBRCA1 cells following in vivo and in vitro exposure of tumor cells to CDDP. Differential in vivo sensitivity was evaluated in xenografted tumors in SCID mice after 4 weeks of treatment with CDDP (5 mg/kg) or vehicle. Tumors were retrieved from animals 4 hours after the last dose of the drug or vehicle. In vitro data were obtained exposing HCC1937 and HCC1937/wtBRCA1 cell lines to CDDP at IC50 doses of 30 and 70mM, or at 60 and 140hM respectively, for 3 and 12 hours. Gene expression profiling was performed by Affymetrix technology using GeneArray 1.0ST. Array data were analyzed using Gene Expression Console, GeneSpring software and Ingenuity Pathway Analysis (IPA). The search for canonical pathways by IPA identified an upregulation of G2/M DNA damage checkpoint pathway, in a dose- and timedependent manner, as well as the down regulation of Notch signaling pathway in HCC1937 cells, after treatment with CDDP in vitro. Both pathways were not affected in BRCA1-reconstituted cells. The in vivo data analysis identified, in HCC1937/wtBRCA1 tumors, following CDDP exposure, modulation of pathways involving AKT3 and PRKAR2B, also known as RII-BETA, a cAMP-dependent protein kinase. Our data correlate with previous evidence of AKT as factor of resistance to CDDP. In conclusion functional status of BRCA1 differentially modulates response to CDDP in vitro and in vivo. Signaling pathways involving Notch, AKT and RII-BETA are involved in these events. These findings might be of interest to design novel therapeutic approaches in BRCA1-defective tumors.
|Titolo:||Whole gene expression profiling shows a differential transcriptional response to CISPLATINUM in BRCA-1 defective versus BRCA1-reconstituted breast cancer cells|
|Data di pubblicazione:||2008|
|Appare nelle tipologie:||1.1 Articolo in rivista|