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. Breast cancer is heterogeneous in the development and progression with patients that have histologically indistinguishable tumours showing disparate outcomes. Breast cancer is the 'poster child' for personalised therapy with assessment of biomarkers, including oestrogen receptor (ER), progesterone receptor and human epidermal growth factor receptor 2 directing patients to specific targeted therapies. Although it is impossible to fully ascertain the relative function of earlier detection and improved therapy, mortality rates for breast cancer have shown remarkable improvement. Despite the marked improvements in outcomes, 192 370 new cases of breast cancer are predicted last year in the United States, with an expected death rate of B20% (Jemal et al, 2009). In terms of poor outcomes, therapy resistance and metastasis both remain as critical challenges. Therefore, additional therapeutic targets are required to improve outcomes. As the autotaxin (ATX)-lysophosphatidic acid (LPA) signalling axis is one of the important survival factors and contributes to invasion and metastasis (Mills and Moolenaar, 2003), it warrants investigation both in terms of its function in the initiation and progression of breast cancer and as a novel therapeutic target.

The Y-box binding protein-1 (YB-1) transcription factor is associated with unfavorable clinical outcomes. However, the mechanisms underlying this association remain to be fully elucidated. We demonstrate that YB-1 phosphorylation, indicative of YB-1 activation, is a powerful marker of outcomes for ovarian cancer patients. In ovarian cancer, YB-1 phosphorylation is induced by activation of the lysophosphatidic acid (LPA) receptor (LPAR) via SRC-dependent transactivation of the epidermal growth factor receptor (EGFR) that is coupled to MAPK/p90 ribosomal S6 kinase (p90RSK), but not phosphatidylinositol 3-kinase (PI3K)/AKT signaling. Activation of the LPAR/SRC/EGFR/MAPK/p90RSK/YB-1 axis leads to production of the EGFR ligand amphiregulin (AREG). AREG induces ongoing YB-1 phosphorylation as well as YB-1-dependent AREG expression thus constituting an AREG/YB-1 self-reinforcing loop. Disruption of transactivation of the EGFR and the downstream self-reinforcing loop decreases invasiveness of ovarian cancer cells in vitro and limits ovarian cancer growth in xenograft models. These findings established the regulation and significance of YB-1 phosphorylation, therefore further exploration of this signaling axis as a therapeutic avenue in ovarian cancer is warranted.