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

Guanmin Meng,Jennifer Dufour,Xiaoyun Tang,Frank Wuest,David Murray,Melinda Wuest,Todd P.W Mcmullen,David N Brindley

doi:10.3390/cancers12040999

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.

Highlights

About 60% of breast cancer patients receive breast-conserving surgery followed by radiation therapy (RT)
RT-induced fibrosis contributes to the development of lymphedema, which results in impaired function and decreased quality of life [8]
We showed that DEX attenuated the RT-induced activation of the ATX-LPA-inflammatory cycle in cultured human adipose tissue after a single γ-ray exposure and in vivo in a breast fat pad of female mice after fractionated X-ray exposures

Summary

Introduction

About 60% of breast cancer patients receive breast-conserving surgery (lumpectomy) followed by radiation therapy (RT). Conventional RT for breast cancer involves irradiating the whole post-surgical breast with daily fractions of 1.8–2 Gy/fraction to a total dose of 45–50 Gy, the most recent. ASTRO guidelines for women with invasive breast cancer recommend hypo-fractionated RT with either. Fibrosis is a common late complication associated with RT [2,3,4]. The frequency of RT-induced breast fibrosis is typically in the range of 15–28% [4,5,6]. Cancers 2020, 12, 999 requires remediation with cosmetic surgery in severe cases [7]. RT-induced fibrosis contributes to the development of lymphedema, which results in impaired function and decreased quality of life [8]

Methods

Results

Conclusion