Poor response to chemotherapy in patients with breast cancer is often associated with overexpression of HER -2 / neu. Interference with HER -2 mRNA translation by means of antisense oligonucleotides might improve the efficacy of chemotherapy. To test this hypothesis, eight breast cancer cell lines and a normal human fibroblast cell line were examined for their level of HER -2 expression, their sensitivity to phosphorothioate antisense oligonucleotides ( AS HER -2 ODN ), and to various chemotherapeutic agents, and the combination of the two. No correlation was found between the intrinsic HER -2 level and either the sensitivity to a particular chemotherapeutic agent alone, or the amount of growth inhibition observed with a specific AS HER -2 ODN concentration. Although sequence specificity and extent of AS HER -2 ODN inhibition of HER -2 synthesis were somewhat higher in the HER -2 overexpressing MDA -MB -453 and SK -BR -3 cells, we found that antisense treatment significantly sensitized all of the breast cancer cells, even MDA -MB -231 and MDA -MB -435 cells, with approximately basal levels of HER -2, to various chemotherapeutic agents. In addition, the combination of AS HER -2 ODN and taxol was shown to synergistically induce apoptosis in MDA -MB -435. These results demonstrate that overexpression of HER -2 would not be a prerequisite for the effective use of AS HER -2 ODN as a combination treatment modality for breast cancer and suggest that the use of AS HER -2 ODN, as part of a combination treatment modality, need not be limited to breast tumors that display elevated levels of HER -2. Cancer Gene Therapy ( 2001 ) 8, 728 -739