Lysophosphatidic acid production and action: critical new players in breast cancer initiation and progression

Abstract

Lysophosphatidic acid (LPA) is a potent lipid mediator that acts on a series of specific G protein-coupled receptors, leading to diverse biological actions. Lysophosphatidic acid induces cell proliferation, survival and migration, which are critically required for tumour formation and metastasis. This bioactive lipid is produced by the ectoenzyme lysophospholipase D or autotaxin (ATX), earlier known as an autocrine motility factor. The ATX-LPA signalling axis has emerged as an important player in many types of cancer. Indeed, aberrant expression of ATX and LPA receptors occurs during the development and progression of breast cancer. Importantly, expression of either ATX or LPA receptors in the mammary gland of transgenic mice is sufficient to induce the development of a high frequency of invasive and metastatic mammary cancers. The focus of research now turns to understanding the mechanisms by which ATX and LPA promote mammary tumourigenesis and metastasis. Targeting the ATX-LPA signalling axis for drug development may further improve outcomes in patients with breast cancer.

Figure 1

Current understanding of breast cancer progression mediated by ATX–LPA signalling axis. Autotaxin and LPA1–3 receptors are expressed in mammary glands and can exert multiple effects under physiological conditions. Lysophosphatidic acid is produce from lysophosphatidylcholine (LPC) by ATX and acts on the EDG-family LPA receptors, LPA1, LPA2 and LPA3. As an important pathway promoting cell survival, the ATX–LPA signalling axis may initiate tumourigenesis in breast by allow cells to be susceptible to other genetic mutations, leading to accumulation of several aberrant signalling pathways. Indeed, each of these components of the ATX–LPA signalling axis sufficiently induces tumourigenesis through upregulation of many signalling pathways, including PI3K, MAPK, Wnt/β-catenin and ER. In addition, marked increase in the production of several cytokines by LPA further advance the disease progression by local inflammation and angiogenesis. The effects of LPA on cytokine production and blood vessel formation may contribute to the metastasis of breast tumours to other tissues such as bone.