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

Abstract

Lysophosphatidic acid (LPA), acting in an autocrine or paracrine fashion through G protein-coupled receptors, has been implicated in many physiological and pathological processes including cancer. LPA is converted to lysophosphatidylcholine (LPC) by the secreted phospholipase, autotaxin (ATX). Although various cell types can produce ATX, adipocyte-derived ATX is believed to be the major source of circulating ATX and also to be the major regulator of plasma LPA. In addition to ATX, adipocytes secrete numerous other factors (adipokines); although several adipokines have been implicated in breast cancer biology, the contribution of mammary adipose tissue-derived LPC/ATX/LPA (LPA-axis) signaling to breast cancer is poorly understood. Using mammary fat-conditioned medium, we investigated the contribution of LPA signaling to mammary epithelial cancer cell biology and identified LPA signaling as a significant contributor to the oncogenic effects of the mammary adipose tissue secretome. To interrogate the role of mammary fat in the LPA-axis during breast cancer progression, we exposed mammary adipose tissue to secreted factors from estrogen receptor-negative mammary epithelial cell lines and monitored changes in the mammary fat pad LPA-axis. Our data indicate that bidirectional interactions between mammary cancer cells and mammary adipocytes alter the local LPA-axis and increase ATX expression in the mammary fat pad during breast cancer progression. Thus, the LPC/ATX/LPA axis may be a useful target for prevention in patients at risk of ER-negative breast cancer.

Dexamethasone Attenuates X-Ray-Induced Activation of the Autotaxin-Lysophosphatidate-Inflammatory Cycle in Breast Tissue and Subsequent Breast Fibrosis

“…The resulting LPA is then able to activate LPA receptor-mediated signaling in the tumor cells. This bi-directional signaling between adipose tissue and breast tumors has been confirmed by other investigators [34,35]. Indeed, adipocytes produce~40% of the body's ATX [36,37] and the breast is rich in adipose tissue.We subsequently showed that exposing cultured human breast adipose tissue to γ-radiation increased the secretion of ATX as well the expression of LPA 1 and LPA 2 receptors downstream of DNA damage [21].…”

Autotaxin and Breast Cancer: Towards Overcoming Treatment Barriers and Sequelae

“…This amplifies the inflammatory cycle and promotes accumulation of inflammatory leukocytes in the inflamed adipose tissue [30,32]. Bi-directional signaling between breast tumors and surrounding adipose tissue through the ATX-LPA-inflammatory cycle ( Figure 3) has been confirmed [81,82]. At the organism level, we showed this increased ATX activity is measurable in the plasma of mice with advanced breast cancer [29].…”

Reduced levels of N’-methyl-2-pyridone-5-carboxamide and lysophosphatidylcholine 16:0 in the serum of patients with intrahepatic cholangiocarcinoma, and the correlation with recurrence-free survival

“…Lysophosphatidic acid (LPA; monoacyl-glycerol-3-phosphate) serves as a mitogen and a stimulator of motility in many cell types [ 24 ], acting in either an autocrine or paracrine fashion via G protein-coupled receptors. LPA is involved in many physiological and pathological processes, including cancer [ 25 ]. LPA enhances tumor growth, metastasis, and chemoresistance [ 26 ].…”

“…LPA is derived from lysophosphatidylcholine (LPC) via the action of a secreted phospholipase termed autotaxin (ATX), which was originally identified as an “autocrine motility factor” of tumor cells [ 24 ]. As ATX promotes both tumor formation and angiogenesis [ 24 ], and as ATX levels are elevated in several human malignancies [ 24 , 27 ], many researchers believe that ATX may be a promising therapeutic target in patients with chronic inflammation and cancer [ 25 , 26 , 28 – 30 ].…”