The LPA1/ZEB1/miR-21-activation pathway regulates metastasis in basal breast cancer

Abstract

Lysophosphatidic acid (LPA) is a bioactive lipid promoting cancer metastasis. LPA activates a series of six G protein-coupled receptors (LPA1-6). While blockage of LPA1 in vivo inhibits breast carcinoma metastasis, down-stream genes mediating LPA-induced metastasis have not been yet identified. Herein we showed by analyzing publicly available expression data from 1488 human primary breast tumors that the gene encoding the transcription factor ZEB1 was the most correlated with LPAR1 encoding LPA1. This correlation was most prominent in basal primary breast carcinomas and restricted to cell lines of basal subtypes. Functional experiments in three different basal cell lines revealed that LPA-induced ZEB1 expression was regulated by the LPA1/Phosphatidylinositol-3-Kinase (Pi3K) axis. DNA microarray and real-time PCR analyses further demonstrated that LPA up-regulated the oncomiR miR-21 through an LPA1/Pi3K/ZEB1-dependent mechanism. Strikingly, treatment with a mirVana miR-21 inhibitor, or silencing LPA1 or ZEB1 completely blocked LPA-induced cell migration in vitro, invasion and tumor cell bone colonization in vivo, which can be restored with a mirVana miR-21 mimic. Finally, high LPAR1 expression in basal breast tumors predicted worse lung-metastasis-free survival. Collectively, our results elucidate a new molecular pathway driving LPA-induced metastasis, thus underscoring the therapeutic potential of targeting LPA1 in patients with basal breast carcinomas.

Metastasis: new functional implications of platelets and megakaryocytes

“…Coincubation of platelets with metastatic breast cancer cells under both steering 38 and passive 39 conditions mediate lysophosphatidic acid (LPA) production that subsequently activates tumor LPA 1 receptor promoting cell invasion via a PI3K/zinc finger E-box-binding homeobox 1/microRNA-21-dependent signaling pathway. 40 The physical interaction between platelets and tumor cells is a wellknown prerequisite for platelet prometastatic activity mediating secretion of protumoral factors. However, secretion of paracrine components active on tumor cells might not be the sole mechanism in platelet-promoting metastasis.…”

“…24 Released PDGF can activate Notch1 and STAT1 signaling pathways, inducing and/or maintaining EMT on CTCs. 25,26 Direct interaction of platelet membranes exposes active P-selectin and GPIIb-IIIa, 41 and the secretion of LPA by activated platelets supports CTC invasion 39,40 and ATP promotes transendothelial cell migration. 37 Figure was generated using the database of images from Servier Medical Art from Servier (http://creativecommons.org/licenses/by/3.0/fr/).…”

MicroRNA-661 promotes non-small cell lung cancer progression by directly targeting RUNX3

“…Increasing evidence has shown that more than half of miRNA genes are located at fragile sites (12)(13)(14). Several studies reported that numerous miRNAs are aberrantly expressed in various human cancers and play significant roles in tumourigenesis and tumour development, including NSCLC (15)(16)(17). Obviously, miRNAs can function as either tumour suppressors or oncogenes in different human cancers depending on the characteristics of their target genes (18).…”

Grainyhead-like 2 in development and cancer

“…38,39 High expression of ZEB1 is associated with low expression of E-Cadherin and advanced diseases of many tumors. [40][41][42][43] GRHL2 can suppress EMT by inhibition of ZEB1 expression via direct repression of the ZEB1 promoter or by impairment of the Six1 and DNA complex in breast cancer. Over expression of GRHL2 induces mesenchymal-to-epithelial transition (MET) of breast cancer cells.…”