The human
epidermal growth factor receptor 2 (HER2)‑targeting agent,
lapatinib, combined with oral fluoropyrimidine
capecitabine, has been previously demonstrated to be an effective treatment option for patients with trastuzumab‑resistant HER2‑positive metastatic
breast cancer. To investigate the molecular mechanisms associated with the interactions between
lapatinib and
capecitabine, the effect of treatment with
lapatinib and phosphatidylinositol‑4,5‑bisphosphate 3‑kinase (PI3K) inhibitors on the expression of
E2F transcription factor 1 (E2F1) and
thymidylate synthase (TS), which is associated with an increased response to 5‑fluorouracil (5‑FU)‑based
chemotherapy, was determined in HER2‑positive
breast cancer cells. The results of reverse transcription‑quantitative polymerase chain reaction demonstrated that administration of
lapatinib and PI3K inhibitors decreased the
mRNA expression of TS and E2F1, a
transcription factor that promotes TS gene expression, in SKBR3 and T47D cell lines. Furthermore, treatment with
lapatinib and PI3K inhibitors also suppressed the
mRNA expression of
ribonucleotide reductase M1 subunit (RRM1), an important determinant of
gemcitabine resistance, and
DNA topoisomerase II‑α (TOP2A), a molecular target of
anthracyclines, in SKBR3 and T47D cell lines. Western blot analysis further demonstrated that the phosphorylation of Akt was inhibited by
lapatinib, and the results of the MTT assay revealed that the combination of
lapatinib with either 5‑FU or
gemcitabine demonstrated synergistic antitumor effects, whereas a combinatory treatment of
lapatinib with
epirubicin, a typical
anthracycline drug, exhibited antagonistic antitumor effects in HER2‑positive
breast cancer cells. These results indicate that the synergistic antitumor effects exhibited by combinatory treatment of
lapatinib with
capecitabine may be induced via the suppression of E2F1‑mediated TS expression.