Lysophosphatidic acid receptor and Ral signaling in breast cancer cell migration and invasion

Abstract

Lysophosphatidic acid (LPA) is a simple lipid molecule that mediates a variety of processes such as cell survival and growth, and plays a role in the progression of a variety of cancers, stimulating cell proliferation, migration and invasion. The effects of LPA are mediated via the activity of its G protein‐coupled receptors, LPA1‐3. Recently, LPA has been shown to enhance metastasis of breast cancer to bone. However, the mechanisms by which LPA receptor signaling regulates cell migration and invasion of breast cancer cells remains unclear. Breast cancer cell proliferation has been shown to be stimulated by the small G protein Ral. Ral activity can be regulated by its guanine‐nucleotide exchange factors (RalGEFs) and the multifunctional protein β‐arrestin. We compared expression of LPA receptors, Ral, RalGDS, and β‐arrestin in the non‐tumorigenic mammary cell line MCF‐10A and the invasive breast cancer cell lines MDA‐MB‐435 and MDA‐MB‐231. Our data shows for the first time that both breast cancer cell lines have higher expression of β‐arrestin compared to MCF‐10A cells. Furthermore, MDA‐MB‐231, but not MCF‐10A cells migrate and invade in response to LPA via pertussis toxin‐sensitive G proteins and via a β‐arrestin‐Ral pathway. In summary, our data demonstrates a novel mechanism by which LPA receptors may regulate breast cancer cell migration and invasion.Research is funded by CIHR awarded to Dr. M Bhattachary