A KLF6 splice variant induces breast cancer metastasis and is associated with poor survival.

  • Major finding: A KLF6 splice variant induces breast cancer metastasis and is associated with poor survival.

  • Mechanism: KLF6-SV1 promotes an EMT-like phenotype and increases cancer cell invasion in part via TWIST1.

  • Impact: KLF6-SV1 identifies invasive tumors and may be a useful therapeutic target to limit metastasis.

Epithelial–mesenchymal transition (EMT) is a critical step in metastasis and is defined by loss of cell–cell adhesion and polarity and increased cell motility and invasion. EMT is accompanied by gene expression changes, including a reduction in E-cadherin levels and induction of mesenchymal markers such as TWIST1, but the factors driving EMT and metastatic growth are not well defined. Hatami and colleagues investigated whether a splice variant of the tumor suppressive transcription factor Krüppel-like factor 6 (KLF6), KLF6-SV1, which is upregulated in many human cancers, contributes to breast cancer metastasis. KLF6-SV1 mRNA expression was highest in hormone receptor–negative primary human breast cancers and was associated with shorter metastasis-free survival and increased risk of metastasis independently of known prognostic factors. In addition, KLF6-SV1 was positively correlated with elevated expression of EMT markers, particularly TWIST1. Consistent with a role for KLF6-SV1 in EMT, overexpression of this oncogenic variant in nontumorigenic mammary epithelial cell lines augmented migration and invasion and triggered an EMT-like phenotype in vitro, with loss of E-cadherin expression and disruption of cell polarity. Moreover, whereas KLF6-SV1 expression did not affect local tumor growth, it was sufficient to induce multiorgan dissemination in subcutaneous and orthotopic mouse models of breast cancer. In contrast, KLF6-SV1 depletion in an aggressive metastatic breast cancer cell line reversed this mesenchymal phenotype, restoring E-cadherin expression and decreasing cell migration and invasion. This regulation of EMT was likely mediated in part by a TWIST1-dependent mechanism, as KLF6-SV1 expression stimulated TWIST1 upregulation in mammary epithelial cells and tumors. Although additional studies are necessary to further elucidate the mechanism by which KLF6-SV1 enhances metastatic potential, these results suggest that this splice variant is an early determinant of invasive disease and that its targeted inhibition may reduce breast cancer metastasis.

Hatami R, Sieuwerts AM, Izadmehr S, Yao Z, Qiao RF, Papa L, et al. KLF6-SV1 drives breast cancer metastasis and is associated with poor survival. Sci Transl Med 2013 Jan 23 [Epub ahead of print].