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

Guanmin Meng; Melinda Wuest; Xiaoyun Tang; Jennifer Dufour; Todd P W McMullen; Frank Wuest; David Murray; David N Brindley

doi:10.3390/cancers12040999

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

Cancers (Basel). 2020 Apr 18;12(4):999. doi: 10.3390/cancers12040999.

Authors

Guanmin Meng^{1

2}, Melinda Wuest^{2

3}, Xiaoyun Tang^{1

2}, Jennifer Dufour³, Todd P W McMullen^{2

4}, Frank Wuest^{2

3}, David Murray^{2

5}, David N Brindley^{1

2}

Affiliations

¹ Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2S2, Canada.
² Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, AB T6G 2S2, Canada.
³ Department of Oncology, Division of Oncologic Imaging, University of Alberta, Edmonton, AB T6G 2R7, Canada.
⁴ Department of Surgery, University of Alberta, Edmonton, AB T6G 2R7, Canada.
⁵ Department of Oncology, Division of Experimental Oncology, University of Alberta, Edmonton, AB T6G 2R7, Canada.

Abstract

We recently showed that radiation-induced DNA damage in breast adipose tissue increases autotaxin secretion, production of lysophosphatidate (LPA) and expression of LPA_1/2 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.

Keywords: adipocytes; adipose tissue; breast cancer; chemokines; cytokines; vasculitis.

Grants and funding

703926/Canadian Cancer Society Research Institute