LIMK2 promotes the metastatic progression of triple-negative breast cancer by activating SRPK1

Parmanand Malvi,Kamaljeet Singh,Suresh Chava,Padmini Manrai,Esther Yoon,Malini Harigopal,Radoslav Janostiak,Narendra Wajapeyee,Romi Gupta

doi:10.1038/s41389-020-00263-1

Parmanand Malvi, Kamaljeet Singh + Show 7 more

Open Access

https://doi.org/10.1038/s41389-020-00263-1

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Abstract

Triple-negative breast cancer (TNBC) is a highly metastatic breast cancer subtype and due to the lack of hormone receptors and HER2 expression, TNBC has limited therapeutic options with chemotherapy being the primary choice for systemic therapy. LIM Domain Kinase 2 (LIMK2) is a serine/threonine kinase that plays an important role in the regulation of actin filament dynamics. Here, we show that LIM domain kinase 2 (LIMK2) is overexpressed in TNBC, and short-hairpin RNA (shRNA)-mediated LIMK2 knockdown or its pharmacological inhibition blocks metastatic attributes of TNBC cells. To determine the mechanism by which LIMK2 promotes TNBC metastatic progression, we performed stable isotope labeling by amino acids in cell culture (SILAC) based unbiased large-scale phosphoproteomics analysis. This analysis identified 258 proteins whose phosphorylation was significantly reduced due to LIMK2 inhibition. Among these proteins, we identified SRSF protein kinase 1 (SRPK1), which encodes for a serine/arginine protein kinase specific for the SR (serine/arginine-rich domain) family of splicing factors. We show that LIMK2 inhibition blocked SRPK1 phosphorylation and consequentially its activity. Furthermore, similar to LIMK2, genetic inhibition of SRPK1 by shRNAs or its pharmacological inhibition blocked the metastatic attributes of TNBC cells. Moreover, the pharmacological inhibition of LIMK2 blocked metastatic progression in mice without affecting primary tumor growth. In sum, these results identified LIMK2 as a facilitator of distal TNBC metastasis and a potential target for preventing TNBC metastatic progression.

Highlights

Breast cancer is the most common cancer diagnosed in women, with an estimated 1.7 million new cases per year worldwide[1]
LIM domain kinase 2 (LIMK2) is overexpressed in triple-negative breast cancer (TNBC) and is necessary for facilitating TNBC metastatic attributes To understand the role of LIMK2 in breast cancer, we first asked whether LIMK2 is overexpressed in breast cancer
Because TNBC is an aggressive breast cancer subtype that currently lacks effective therapeutic approaches, we focused our studies with LIMK2 on TNBC

Summary

Introduction

Breast cancer is the most common cancer diagnosed in women, with an estimated 1.7 million new cases per year worldwide[1]. Molecular genetics studies have classified breast cancer into four major subtypes based on gene expression profiles: luminal A, luminal B, HER2-positive, and basal-like breast cancers[2]. Similar breast cancer subtypes were confirmed by The Cancer Genome Atlas studies[3]. Patient survival and response to therapies varies by breast cancer subtype[4]. The majority of basal-like breast cancer tissue is characterized by the lack of hormone receptors and the absence of HER2 amplification; it is referred to as triple-negative breast cancer (TNBC)[5]. TNBC is an aggressive breast cancer accounting for 15–20% of all breast cancer cases[6]. TNBC is associated with a high mortality rate due in part to the highly metastatic nature of TNBC7, as well as the lack of effective therapies[8]

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