Molecular Basis of LH Action on Breast Cancer Cell Migration and Invasion via Kinase and Scaffold Proteins.

Joselina Magali Mondaca,Ana Carla Castro Guijarro,Marina Inés Flamini,Ivonne Denise Uzair,Angel Matias Sanchez

doi:10.3389/fcell.2020.630147

Abstract

Breast cancer (BC) is a major public health problem affecting women worldwide. Approximately 80% of diagnosed cases are hormone-dependent breast cancers. These hormones are known to stimulate tumor development and progression. In this setting, tentative evidence suggests that luteinizing hormone (LH) may also play a role in tumors. In BC cells that express functional LH receptors (LHR), this hormone regulates cell migration and invasion by controlling several kinases that activate actin cytoskeletal proteins. In this article, we show that LH induces phosphorylation of paxillin and its translocation toward the plasmatic membrane, where focal adhesion complexes are assembled. This process is triggered via a rapid extra-gonadal LHR signaling to Src/FAK/paxillin, which results in the phosphorylation/activation of the nucleation promoter factors cortactin and N-WASP. As a consequence, Arp2/3 complexes induce actin polymerization, essential to promote cell adhesion, migration, and invasion, thus enhancing metastatic spread of tumoral cells. Our findings provide relevant information about how gonadotrophins exert their action in BC. This information helps us understand the extragonadal effects of LH on BC metastasis. It may provide new perspectives for therapeutic treatment, especially for women with high serum levels of gonadotrophins.

Highlights

Women produce a range of reproductive hormones
We have previously reported that N-Wiskott-Aldrich syndrome proteins (WASPs) is phosphorylated after 17β-estradiol and triiodothyronine treatment (Sanchez et al, 2010; Shortrede et al, 2016; Uzair et al, 2019), increasing cell membrane structure formation implicated in cellular movement
As a first approach to establish the extragonadal actions of luteinizing hormone (LH) on Breast cancer (BC) cell motility, T-47D cells were treated with follicular-phase levels of LH (5 mIU/ml) for different times (0–60 min) to analyze the expression and phosphorylation of N-WASP, a key regulator of actin cytoskeleton reorganization (Frugtniet et al, 2015)

Summary

Introduction

Women produce a range of reproductive hormones. Their secretion patterns vary throughout their lifetime. Postmenopausal women have lower estrogen and higher gonadotrophin concentrations, but in general, their hormone levels are fairly constant (Hall et al, 2000; Hernandez et al, 2005). Gonadotrophins, such as follicle-stimulating hormone (FSH) and luteinizing hormone (LH), are glycoproteins that act on the gonads to regulate development and reproduction. These hormones are produced by the anterior pituitary gland.

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