Association of autotaxin and lysophosphatidic acid receptor 3 with aggressiveness of human breast carcinoma

Abstract

In vitro and in vivo experimental studies have demonstrated the role of lysophosphatidic acid (LPA) signaling in tumor proliferation, invasiveness, and metastasis. Among LPA receptors, the overexpression of LPA receptor 3 (LPAR3) in transgenic mice has resulted in the highest rate of breast cancer metastasis. Our goal is to evaluate the LPA-producing enzyme autotaxin and LPAR3 as potential therapeutic targets in breast cancer patients. The expression of autotaxin and LPAR3 was examined by immunohistochemical analysis of 87 invasive human breast carcinomas. Carcinomas were more frequently positive for autotaxin and LPAR3 (24.4 and 43 %, respectively) compared to adjacent normal breast tissue (6.1 and 2.9 %, respectively). Increased stromal autotaxin expression was found in 16.3 % of the tumors. LPAR3 overexpression was associated with less differentiated tumors, human epidermal growth factor receptor 2 expression, and absence of progesterone receptors. The luminal type A carcinomas showed the lowest frequency of autotaxin and LPAR3 expression. Strong desmoplastic stromal reaction was more frequent among the carcinomas with autotaxin-positive tumor cells or autotaxin-positive stroma. Patients with carcinomas overexpressing LPAR3 in epithelial cells or autotaxin in stromal cells were more likely to have larger tumors, nodal involvement, and higher stage disease. Autotaxin overexpression in tumor cells also correlated with tumor size and clinical stage. Our data indicate that the increased expression of LPAR3 and autotaxin in human breast cancer is associated with tumor aggressiveness. They also suggest that LPA mediates tumor metastatic ability and peritumoral desmoplastic reaction through autocrine-paracrine mechanisms. A substantial portion of breast cancer patients might benefit from autotoxin/LPA receptor-targeted therapies.

Mammary Adipose Tissue-Derived Lysophospholipids Promote Estrogen Receptor–Negative Mammary Epithelial Cell Proliferation

“…Qualitatively, TAg mouse mammary fat pads stained much more intensely for ATX and the adipocytes tended to be smaller. These data agree with previous studies suggesting that mammary tumorigenesis increases ATX expression in the mammary stroma (32,38). …”

“…For example, we observed a striking increase in ATX expression in the stromal-compartment of TAg vs. parental mouse mammary glands. Similar observations were made in two other studies, one in human breast cancer and the other in a mouse model (32, 38). In a panel of 87 invasive human breast carcinomas, Popnikolov et al reported increased stromal ATX expression in 16.3% of samples, and high ATX expression was associated with strong desmoplastic stromal reactions (32).…”

“…In Tag MECs, we determined the mRNA expression of the genes encoding LPA receptors 1, 2, and 3 ( edg1 , edg4 , and edg7 ; respectively). These three LPAR isoforms have been implicated in breast cancer progression (14, 15, 31, 32). Transcripts for genes encoding all three receptors were detected (Fig.…”

Lipid phosphate phosphatases and their roles in mammalian physiology and pathology

“…In a colon cancer cell line, LPA increases the synthesis of macrophage migration inhibitory factor, which also promotes tumor growth ( 133 ). Women with breast carcinomas that express high levels of LPA 3 receptors in epithelial cells, or ATX in stromal cells, have larger tumors, nodal involvement, and higher stage disease ( 134 ).…”

Recent advances in targeting the autotaxin-lysophosphatidate-lipid phosphate phosphatase axis in vivo

“…There are also a host of soluble molecules in the tumor and this heterogeneity adds another layer of complexity to ATX/LPA signaling. Popnikolov et al showed that immunohistochemical staining for ATX in stromal cells and LPA 3 and cancer epithelial cells correlate positively with cancer aggressiveness [75] . This study highlights the role of ATX from tumor stroma as a producer of LPA for cancer progression.…”