Tumor suppressor mutant may predict poor outcome in breast cancer

By Sally Robertson, B.Sc.Feb 6 2013

An oncogenic variant of the Krüppel-like family (KLF)6 tumor suppressor gene appears to play a role in driving breast cancer metastasis and may be a prognostic marker for poor patient outcome, report researchers.

Furthermore, the KLF6-SV1 variant provides a potential therapeutic target for invasive breast cancer, they say.

"We demonstrated that KLF6-SV1 overexpression induced an EMT [epithelial-to-mesenchymal transition]-like phenotype and resulted in marked cancer cell dissemination in vivo, independent of cellular proliferation," report the researchers, who point out that EMT is a hallmark and key driver of many of the initial steps in the metastatic cascade.

As reported in Science Translational Medicine, Goutham Narla (Mount Sinai School of Medicine, New York, USA) and colleagues performed multivariate analysis for metastasis-free survival (MFS), according to KLF6-SV1 mRNA levels, in 671 primary breast cancer patients.

They found that increased expression of KLF6-SV1 mRNA in primary tumors was associated with a decreased likelihood for MFS, after adjustment for traditional confounders such as age, menopausal status, tumor size, grade, and steroid hormone receptor levels.

Furthermore, primary tumors that contained a relatively large proportion of stromal cells expressed the highest levels of KLF6-SV1. In addition, KLF6-SV1 mRNA levels were inversely associated with age and steroid hormone receptors, whereas they were positively associated with tumors of a high genomic grade index.

The authors say that these findings are "particularly relevant" because EMT shows similar associations.

To further validate the biological role of KLF6-SV1 in breast cancer progression and metastasis, the researchers performed loss-of-function studies in a highly aggressive and metastatic derivative of a breast cancer cell line.

The researchers found that targeted reduction of KLF6-SV1 resulted in decreased expression of the mesenchymal marker N-cadherin, with a concomitant increase in the epithelial marker E-cadherin.

"Targeted reduction of KLF6-SV1 resulted in the reversion of the mesenchymal-like phenotype to a more epithelial one, similar to a process referred to as mesenchymal-to-epithelial transition," they write.

Next, to identify whether KLF6-SV1-induced EMT could drive the phenotypic switch from indolent, localized breast cancer to highly metastatic lethal disease in vivo, the researchers injected mice with tumorigenic nonmetastatic cells overexpressing KLF6-SV1.

"Remarkably we found that KLF6-SV1 overexpression alone drove the entire metastatic cascade resulting in multiorgan dissemination, including distant metastasis to the liver, kidney, heart, lung, intestinal tract, and spleen," they report.

The researchers say that KLF6-SV1 overexpression in breast cancer patients could potentially identify a distinct population whose tumors might need to be treated more aggressively because of their increased propensity to metastasize.

"This study and others highlight the potential role for therapeutic targeting of KLF6-SV1 in a variety of advance cancers," they conclude.

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