Abstract
The lipid mediator lysophosphatidic acid (LPA) plays a role in cancer progression and signals via specific G protein-coupled receptors, LPA(1-3). LPA has been shown to enhance the metastasis of breast carcinoma cells to bone. However, the mechanisms by which LPA receptors regulate breast cancer cell migration and invasion remain unclear. Breast cancer cell proliferation has been shown to be stimulated by Ral GTPases, a member of the Ras superfamily. Ral activity can be regulated by the multifunctional protein beta-arrestin. We now show that HS578T and MDA-MB-231 breast cancer cells and MDA-MB-435 melanoma cells have higher expression of beta-arrestin 1 mRNA compared with the nontumorigenic mammary MCF-10A cells. Moreover, we found that the mRNA levels of LPA1, LPA2, beta-arrestin 2, and Ral GTPases are elevated in the advanced stages of breast cancer. LPA stimulates the migration and invasion of MDA-MB-231 cells, but not of MCF-10A cells, and this is mediated by pertussis toxin-sensitive G proteins and LPA1. However, ectopic expression of LPA1 in MCF-10A cells caused these cells to acquire an invasive phenotype. Gene knockdown of either beta-arrestin or Ral proteins significantly impaired LPA-stimulated migration and invasion. Thus, our data show a novel role for beta-arrestin/Ral signaling in mediating LPA-induced breast cancer cell migration and invasion, two important processes in metastasis.
Highlights
Lysophosphatidic acid (LPA), in addition to being a key intermediate in de novo lipid synthesis, is a known regulator of LPA and its receptors, LPA1 and LPA2, have been implicated in breast cancer [8]
We examined the expression of these genes by quantitative real-time PCR in a cDNA array comprised of 48 tissue samples taken from patients with stages 0 to IV breast cancer
We have identified, for the first time, that LPA stimulates Ral activity in breast cancer cells to regulate cell migration and invasion and that LPA1 interacts with Ral GTPases
Summary
LPA and its receptors, LPA1 and LPA2, have been implicated in breast cancer [8]. Autotaxin, a key enzyme in LPA production in blood [1, 8], is overexpressed in various human malignancies, including breast cancer, implying the involvement of LPA production and signaling in a variety of human tumors. LPA2 receptors are elevated in invasive ductal carcinomas [13] These studies have indicated an important role for LPA in breast cancer, the specific mechanisms by which LPA and its receptors mediate breast cancer cell migration and invasion, two important processes in cancer metastasis, remain unclear. Ral proteins have been shown to stimulate breast cancer cell proliferation, which can be inhibited by the suppression of Ral activity [16]. We report that the expression of LPA receptors (LPA1 and LPA2), β-arrestins, and Rals is elevated in breast cancer tissue in advanced stages of the disease. We show for the first time that β-arrestins are highly expressed in the highly metastatic MDA-MB-231 breast cancer cells, and LPA1 associates with Ral and can stimulate Ral activity to mediate migration and invasion via a β-arrestin/Ral pathway
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