Expression of Autotaxin⁻Lysophosphatidate Signaling-Related Proteins in Breast Cancer with Adipose Stroma.

Yoon Jin Cha,Ja Seung Koo

doi:10.3390/ijms20092102

Abstract

This research aimed to evaluate the expression and clinical implication of autotaxin (ATX)-lysophosphatidate (LPA) signaling-related proteins in breast cancer with adipose stroma. To this end, a tissue microarray (TMA) was constructed from 137 breast cancer tissues with adipose stroma and 329 breast cancer tissues with non-adipose stroma (inflammatory stroma: n = 81, 24.6%; fibrous stroma: n = 246, 75.4%). Immunohistochemical staining for ATX-LPA signaling-related proteins (ATX, LPA1, LPA2, and LPA3) was performed on the TMA. The results showed that LPA2 in tumor cells and LPA3 in stromal cells were highly expressed in breast cancer with adipose stroma and breast cancer with adipose and inflammatory stroma, respectively. Stromal LPA1 positivity (p = 0.017) and stromal LPA3 positivity (p = 0.004) were higher in breast cancer with adipose stroma containing CD68-positive crown-like structures (CLS). Stromal ATX positivity (p = 0.010) and stromal LPA3 positivity (p = 0.009) were higher in breast cancer with adipose tissue containing CD163-positive CLS. In breast cancer with adipose stroma, the number of CD163-positive macrophages was greater with stromal ATX positivity (p = 0.003), and the number of CD68-positive and CD163-positive macrophages were greater in cases with stromal LPA3 positivity. In conclusion, ATX-LPA signaling-related proteins are highly expressed in breast cancer with adipose stroma, with associated macrophage infiltration.

Highlights

Autotaxin (ATX) is a glycoprotein encoded by the ENPP2 gene located on chromosome 8 [1]
We investigated the expression of ATX-LPA signaling-related proteins in breast cancer with adipose stroma
Higher LPA2 expression in tumor cells of breast cancer with adipose stroma may be affected by interactions between cancer cells and cancer-associated adipocytes (CAAs)

Summary

Introduction

Autotaxin (ATX) is a glycoprotein encoded by the ENPP2 gene located on chromosome 8 [1]. LPA binds to LPA receptors; activates phospholipase C and the MAPK, PI3K, and PhoA pathways; and is involved in various cellular processes [2,3]. The ATX-LPA signaling axis is closely related to tumor biology, including tumor formation, progression, and metastasis [5,6]. ATX is generated from platelets, endothelial cells, fibroblasts, and adipocytes [7,8,9,10], and ATX from adipocytes has an impact on plasma LPA level [11]. Adipocytes could be an important origin of ATX in tumors. Breast cancer is a human cancer that has adipocyte-rich stroma. ATX-LPA signaling has been reported to be involved in angiogenesis, tumor cell invasion, and migration in breast cancer [14]

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