HER2/neu Oncogene and Sensitivity to the DNA-Interactive Drug Doxorubicin

Abstract

Breast tumor cells overexpressing the proto-oncogene HER2/neu are known to be less responsive to certain DNA-binding chemotherapeutic agents. The current study specifically investigates the correlation between chemosensitivity to the DNA-binding drug doxorubicin and cellular HER2/neu protein levels in a panel of eight breast cancer cell lines (HS-578, BT-474, MDA-MB-453, MDA-MB-231, MDA-MB-175, MCF-7, ZR-75-1 and T47D). The IC50 (the drug concentration required to inhibit cell growth by 50%) values for the cell lines were determined by the sulforhodamine B assay. IC50 values were correlated with HER2/neu protein levels determined by Western blotting. An almost linear relationship between IC50 and HER2/neu protein level for seven cell lines (p = 0.02, r2 = 0.680) was found, with protein levels increasing as resistance increased. The findings suggest that overexpression of HER2/neu correlates with increased resistance to doxorubicin in seven of eight breast cancer cell lines studied. The observation that, in one cell line (MDA-MB-175), doxorubicin IC50 did not correlate with HER2/neu levels, suggests that in these cells, an as-of-yet unidentified factor contributes to resistance. If the observed correlation, which was present in seven of eight cell lines, is confirmed in a larger sample size, increased HER2/neu levels may be implemented as a predictor of breast tumor sensitivity to doxorubicin.

Keywords

• her2/neu oncogene
• breast cancer
• doxorubicin