γKlotho is a novel marker and cell survival factor in a subset of triple negative breast cancers
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Nuša Trošt1,2, Samuel Peña-Llopis2, Sajjan Koirala3, Jurij Stojan1, Patrick Ryan Potts3, Klementina Fon Tacer3, Elisabeth D. Martinez2,4
1Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
2Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
3Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
4Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA
Elisabeth D. Martinez, e-mail: firstname.lastname@example.org
Klementina Fon Tacer, e-mail: email@example.com
Keywords: LCTL; gamma Klotho; FGF; breast cancer; cancer therapy; ROS; oxidative stress; oncogene
Received: May 05, 2015 Accepted: October 30, 2015 Published: November 09, 2015
Over the last decade, breast cancer mortality has declined. However, triple negative breast cancer (TNBC) remains a challenging problem mostly due to early recurrence and lack of molecularly driven treatments. There is a critical need to identify subgroups of TNBC with common molecular features that can be therapeutically targeted. Here we show that in contrast to Klotho and βKlotho, the third member of the Klotho protein family, γKlotho, is overexpressed in more than 60% of TNBCs and correlates with poorer disease progression. Furthermore, we find that γKlotho is expressed in a subset of TNBC cell lines promoting cell growth. Importantly, we demonstrate that in these cells γKlotho is necessary for cell survival and that its depletion leads to constitutive ERK activation, cell cycle arrest and apoptosis. Interestingly, we observe increased oxidative stress in γKlotho-depleted cells suggesting that γKlotho enables cancer cells to cope with an oxidative environment and that cells become dependent on its expression to maintain this survival advantage. These findings indicate that γKlotho might be a potential marker for patients that would benefit from treatments that alter oxidative stress and constitutes a novel drug target for a subset of TN breast cancers.
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