Abstract
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.
