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

Abstract

We recently showed that radiation-induced DNA damage in breast adipose tissue increases autotaxin secretion, production of lysophosphatidate (LPA) and expression of LPA1/2 receptors. We also established that dexamethasone decreases autotaxin production and LPA signaling in non-irradiated adipose tissue. In the present study, we showed that dexamethasone attenuated the radiation-induced increases in autotaxin activity and the concentrations of inflammatory mediators in cultured human adipose tissue. We also exposed a breast fat pad in mice to three daily 7.5 Gy fractions of X-rays. Dexamethasone attenuated radiation-induced increases in autotaxin activity in plasma and mammary adipose tissue and LPA1 receptor levels in adipose tissue after 48 h. DEX treatment during five daily fractions of 7.5 Gy attenuated fibrosis by ~70% in the mammary fat pad and underlying lungs at 7 weeks after radiotherapy. This was accompanied by decreases in CXCL2, active TGF-β1, CTGF and Nrf2 at 7 weeks in adipose tissue of dexamethasone-treated mice. Autotaxin was located at the sites of fibrosis in breast tissue and in the underlying lungs. Consequently, our work supports the premise that increased autotaxin production and lysophosphatidate signaling contribute to radiotherapy-induced breast fibrosis and that dexamethasone attenuated the development of fibrosis in part by blocking this process.

Lipid Phosphate Phosphatases and Cancer

“…Dexamethasone, an anti-inflammatory glucocorticoid, attenuates the RT-induced upregulation of the expression ATX and LPA1R and LPA2R and increases LPP1 expression [ 156 ], which together decrease LPA signaling. Pulmonary fibrosis caused by RT or bleomycin is also blocked by dexamethasone [ 157 , 158 , 159 ].…”

Role of Adipose Tissue-Derived Autotaxin, Lysophosphatidate Signaling, and Inflammation in the Progression and Treatment of Breast Cancer

“…We, therefore, used normal Balb/c mice and the orthotopic 4T1-Balb/c mouse syngeneic model of breast cancer to study how the effects of DEX on LPA signaling could modify RT-induced fibrosis. DEX treatment during fractionated RT attenuated fibrosis in the irradiated fat pad of Balb/c mice by ~70% at 7 weeks following the irradiation [ 146 ]. DEX treatment decreased plasma ATX activity at 2 days after 3 fractions of RT by ~43% in normal mice, but ATX activity in the plasma returned to non-DEX treatment levels at 7 weeks after 5 fractions of RT.…”

“…DEX treatment decreased plasma ATX activity at 2 days after 3 fractions of RT by ~43% in normal mice, but ATX activity in the plasma returned to non-DEX treatment levels at 7 weeks after 5 fractions of RT. Total ATX activities in the irradiated fat pad and lungs were also not changed significantly after seven weeks following treatment with DEX [ 146 ]. Despite this, there was a change in the distribution of ATX in the adipose tissue and lungs.…”

“…This distribution reflected that of fibrous tissue in fat pads and lungs. This association of ATX with blood vessels was attenuated by DEX along with the decreased fibrotic response [ 146 ]. ATX-LPA signaling through LPA1 receptors is critical for vascular development [ 147 ] and vasculitis [ 148 , 149 ].…”

“…Secondly, the therapeutic effects of DEX in decreasing lung fibrosis were found not to be temporally robust in previous work [ 154 , 156 , 157 ]. Thus, it will likely be far more advantageous to target the ATX-LPA-inflammatory axis more specifically and directly [ 146 ].…”