Stathmin is the founding member of a family of microtubule-destabilizing
proteins that have a critical role in the regulation of mitosis.
Stathmin is expressed at high levels in
breast cancer and its overexpression is linked to
disease progression. Although there is a large body of evidence to support a role for
stathmin in
breast cancer progression, the validity of
stathmin as a viable therapeutic target for
breast cancer has not been investigated. Here, we used a bicistronic adenoviral vector that co-expresses
green fluorescent protein and a
ribozyme that targets
stathmin messenger RNA in preclinical
breast cancer models with different
estrogen receptor (ER) status. We examined the effects of anti-
stathmin ribozyme on the malignant phenotype of
breast cancer cells in vitro and in xenograft models in vivo both as a single agent and in combination with chemotherapeutic agents. Adenovirus-mediated gene transfer of anti-
stathmin ribozyme resulted in a dose-dependent inhibition of proliferation and clonogenicity associated with a G2/M arrest and increase in apoptosis in both ER-positive and ER-negative
breast cancer cell lines. This inhibition was markedly enhanced when
stathmin-inhibited
breast cancer cells were exposed to low concentrations of
taxol, which resulted in virtually complete loss of the malignant phenotype. Interestingly,
breast cancer xenografts treated with low doses of anti-
stathmin therapy and
taxol showed regression in a majority of
tumors, while some
tumors stopped growing completely. In contrast, combination of anti-
stathmin ribozyme and
adriamycin resulted in only a modest inhibition of growth in vitro and in
breast cancer xenografts in vivo. Although inhibition of
tumor growth was observed in both the combination treatment groups compared with groups treated with single agent alone, combination of anti-
stathmin therapy and
taxol had a more profound inhibition of tumorigenicity, as both agents target the microtubule pathway. Clinically, these findings are highly relevant because
taxol is one of the most active chemotherapeutic agents in
breast cancer. These studies provide the proof-of-principle that
stathmin provides an attractive molecular target, which could serve as a primary focus of novel approaches to
breast cancer.