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. 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.

Serum Lysophosphatidic Acid Level in Chronic Myeloid Leukemia

“…In this study, there was a significant difference in the serum levels of LPA between patient and control groups, which was higher in patients with CML than in healthy subjects. This result has been observed by many studies of other cancers (11,12).…”

Lysophosphatidic acid receptor isoforms expression in prostate cancer cells is differentially regulated by the CYP17A1 inhibitor abiraterone and depends on the androgen receptor

“…Therefore, AA-driven modulation of LPAR isoforms is more likely due to the control of LPAR expression than to the regulation of LPAR ligand synthesis by autotaxin catalysis. Studies of a breast cancer model confirmed this assumption, since LPAR expression has been shown to be linked to steroid hormone production and estrogen receptor activity [12,26] . The LPA receptors' mRNA expression pattern in PC cell lines PC-3 and LNCaP was shown for LPAR1-4.…”

Lysophosphatidic acid receptor 1 suppression sensitizes rheumatoid fibroblast‐like synoviocytes to tumor necrosis factor–induced apoptosis

“…The effect of LPA in the promotion of the proliferation of several cell types, especially cancer cells (21)(22)(23)(24), is well known. However, LPA may have negative effects on cell growth, as in myeloma, or it may have no effect at all, as in astrocytes and Jurkat cells (25).…”