PTEN acts as a phosphatidylinositol phosphatase with a possible role in the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. Mutations in PTEN are frequent and their presence is associated with poor prognosis in breast cancer, which is the most common type of non-cutaneous malignancy in females. Delivery of the tumor suppressor PTEN gene represents a powerful strategy for breast cancer therapy, but a present limitation of gene therapy is the ability to deliver sufficient quantities of active proteins to target cells. The capacity of HSV-1VP22 fusion proteins to spread from the primary transduced cell to surrounding cells could improve gene therapeutics, particularly in cancer. To assess the potential efficacy of VP22 as a gene therapy for breast cancer, expression vectors for N- and C-terminal PTEN-VP22 fusion proteins were constructed. VP22‑mediated intercellular transport and antitumor efficacy in BT549 (PTEN-null) breast tumor cells were investigated. The results showed that PTEN-VP22 has the same spreading abilities as VP22. In cell proliferation and apoptosis assays, PTEN-VP22 gene transfer induces a stronger anti-proliferative effect and apoptotic activity compared with PTEN gene transfer alone. In addition, VP22 enhanced the PTEN‑mediated decrease in the level of phosphorylated AKT. The results show that PTEN-VP22 can spread in vitro and PTEN-VP22 gene induces significantly greater antitumor activity than the PTEN gene alone. This study confirms the utility of VP22-mediated delivery in vitro and suggests that PTEN-VP22 may have applications in breast cancer gene therapy.