Autotaxin and Lysophosphatidate Signaling: Prime Targets for Mitigating Therapy Resistance in Breast Cancer

Abstract

Overcoming and preventing cancer therapy resistance is the most pressing challenge in modern breast cancer management. Consequently, most modern breast cancer research is aimed at understanding and blocking these therapy resistance mechanisms. One increasingly promising therapeutic target is the autotaxin (ATX)-lysophosphatidate (LPA)-lipid phosphate phosphatase (LPP) axis. Extracellular LPA, produced from albumin-bound lysophosphatidylcholine by ATX and degraded by the ecto-activity of the LPPs, is a potent cell-signaling mediator of tumor growth, invasion, angiogenesis, immune evasion, and resistance to cancer treatment modalities. LPA signaling in the post-natal organism has central roles in physiological wound healing, but these mechanisms are subverted to fuel pathogenesis in diseases that arise from chronic inflammatory processes, including cancer. Over the last 10 years, our understanding of the role of LPA signaling in the breast tumor microenvironment has begun to mature. Tumor-promoting inflammation in breast cancer leads to increased ATX production within the tumor microenvironment. This results in increased local concentrations of LPA that are maintained in part by decreased overall cancer cell LPP expression that would otherwise more rapidly break it down. LPA signaling through six G-protein-coupled LPA receptors expressed by cancer cells can then activate virtually every known tumorigenic pathway. Consequently, to target therapy resistance and tumor growth mediated by LPA signaling, multiple inhibitors against the LPA signaling axis are entering clinical trials. In this review, we summarize recent developments in LPA breast cancer biology, and illustrate how these novel therapeutics against the LPA signaling pathway may be excellent adjuncts to extend the efficacy of evolving breast cancer treatments.

Targeting Sphingosine-1-Phosphate Signaling in Breast Cancer

“…Recently, lipid mediators have attracted attention as signaling molecules that play important roles in cancer [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. Among the lipid mediators, sphingosine-1-phosphate (S1P) is a key molecule with a variety of bioactive activities, including those involved in cancer cell proliferation, invasion, and metastasis; S1P has also been shown to contribute to the formation of the cancer microenvironment by inducing surrounding vascular- and lymph-angiogenesis and regulating the immune system [ 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ].…”