LRP5 regulates the expression of STK40, a new potential target in triple-negative breast cancers.

Sylvie Maubant,Bruno Tesson,Thierry Dubois,Francisco Cruzalegui,Aurélie Dumont,Sergio Roman-Roman,David Gentien,Amélie Brisson,Sardar Faisal Mahmood,Maïté Noizet,Bérengère Marty-Prouvost,Leanne De Koning,Gordon C Tucker,Virginie Maire,Fariba Némati,Guillem Rigaill,Didier Decaudin,Tania Tahtouh,Mengliang Ye

doi:10.18632/oncotarget.25187

Abstract

Triple-negative breast cancers (TNBCs) account for a large proportion of breast cancer deaths, due to the high rate of recurrence from residual, resistant tumor cells. New treatments are needed, to bypass chemoresistance and improve survival. The WNT pathway, which is activated in TNBCs, has been identified as an attractive pathway for treatment targeting. We analyzed expression of the WNT coreceptors LRP5 and LRP6 in human breast cancer samples. As previously described, LRP6 was overexpressed in TNBCs. However, we also showed, for the first time, that LRP5 was overexpressed in TNBCs too. The knockdown of LRP5 or LRP6 decreased tumorigenesis in vitro and in vivo, identifying both receptors as potential treatment targets in TNBC. The apoptotic effect of LRP5 knockdown was more robust than that of LRP6 depletion. We analyzed and compared the transcriptomes of cells depleted of LRP5 or LRP6, to identify genes specifically deregulated by LRP5 potentially implicated in cell death. We identified serine/threonine kinase 40 (STK40) as one of two genes specifically downregulated soon after LRP5 depletion. STK40 was found to be overexpressed in TNBCs, relative to other breast cancer subtypes, and in various other tumor types. STK40 depletion decreased cell viability and colony formation, and induced the apoptosis of TNBC cells. In addition, STK40 knockdown impaired growth in an anchorage-independent manner in vitro and slowed tumor growth in vivo. These findings identify the largely uncharacterized putative protein kinase STK40 as a novel candidate treatment target for TNBC.

Highlights

Breast cancer is the most common type of cancer in women
We investigated the similarity of their expression in each Triple-negative breast cancers (TNBCs) sample (Figure 1C)
LRP5 DNA copy number (CN) in TNBC was higher than that in luminal A tumors only (Figure 1D), but lipoprotein receptorrelated protein 6 (LRP6) DNA CN was higher in TNBC than in the other breast cancer subtypes (Figure 1E)

Summary

Introduction

Breast cancer is the most common type of cancer in women. It is a heterogeneous disease, with four main subtypes defined on the basis of gene expression profiles: luminal A, luminal B, human epidermal growth factor receptor 2 (HER2)-overexpressing and basal-like [1, 2]. Basal-like tumors resemble triple-negative breast cancers (TNBCs), which pathologists identify on the basis of their absence of expression of estrogen (ER) and progesterone receptors and lack of HER2 overexpression [7, 8]. TNBC patients respond well to conventional chemotherapies, but this subtype accounts for a large proportion of breast cancer deaths, due to high rates of recurrence from residual, resistant tumor cells [8]. New treatments are required, to overcome chemoresistance and improve survival [4, 5, 7, 9,10,11]

Methods

Results

Conclusion