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 LPA1in 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.
Highlights
Lysophosphatidic acid (LPA) is a naturally occurring bioactive lipid promoting cancer progression and metastasis [1, 2]
We found that the correlation between LPAR1 and ZEB1 was stronger in the basal subtype (R Spearma n = 0.59) of human primary breast tumors than the non-basal subtype (R Spearma n = 0.40) (Figures 1a and 1b)
Integrating genetic and pharmacological approaches in vitro and in vivo we demonstrate that the proinvasive activity of LPA on triple negative breast cancer cells depends on an LPA1/PI3K/ZEB1/miR-21 activation cascade
Summary
Lysophosphatidic acid (LPA) is a naturally occurring bioactive lipid promoting cancer progression and metastasis [1, 2]. Pharmacological blockage of LPA receptors with the pan-LPA antagonist BrP-LPA inhibits human breast MDA-MB-231 cancer cell motility in vitro and promotes tumor regression associated with a decrease in blood vessel density surrounding the tumors in a mouse xenograft model, suggesting that LPA signaling may be a potential therapeutic target for patients with breast cancers [3]. Studies showed that induction of LPA1 expression induces metastasis in breast and ovarian cancer cells [5, 6] and stimulates in the motility of human pancreatic cancer cells [7]. Using immune compromised mice we demonstrated that expression of this receptor confers a high propensity to human breast cancer cells to induce bone metastasis [8]
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