Decorin, an exercise-induced secretory protein, is associated with improved prognosis in breast cancer patients but does not mediate anti-tumorigenic tissue crosstalk in mice

Marit Hjorth; Casey L Egan; Guilherme D Telles; Martin Pal; David Gallego-Ortega; Oliver K Fuller; Emma D McLennan; Ryan D Gillis; Tae Gyu Oh; George E O Muscat; Surafel Tegegne; Michael Sm Mah; Joanna Skhinas; Emma Estevez; Timothy E Adams; Matthew J McKay; Mark Molloy; Kevin I Watt; Hongwei Qian; Paul Gregorevic; Thomas R Cox; Pernille Hojman; Julie Midtgaard; Jesper F Christensen; Martin Friedrichsen; Renato V Iozzo; Erica K Sloan; Brian G Drew; Jørgen F P Wojtaszewski; Martin Whitham; Mark A Febbraio

doi:10.1016/j.jshs.2024.100991

Decorin, an exercise-induced secretory protein, is associated with improved prognosis in breast cancer patients but does not mediate anti-tumorigenic tissue crosstalk in mice

J Sport Health Sci. 2024 Sep 26:100991. doi: 10.1016/j.jshs.2024.100991. Online ahead of print.

Authors

Marit Hjorth¹, Casey L Egan², Guilherme D Telles³, Martin Pal⁴, David Gallego-Ortega⁵, Oliver K Fuller², Emma D McLennan², Ryan D Gillis², Tae Gyu Oh⁶, George E O Muscat⁷, Surafel Tegegne², Michael Sm Mah², Joanna Skhinas⁸, Emma Estevez⁸, Timothy E Adams⁹, Matthew J McKay¹⁰, Mark Molloy¹⁰, Kevin I Watt¹¹, Hongwei Qian¹², Paul Gregorevic¹², Thomas R Cox⁸, Pernille Hojman¹³, Julie Midtgaard¹³, Jesper F Christensen¹³, Martin Friedrichsen¹⁴, Renato V Iozzo¹⁵, Erica K Sloan², Brian G Drew¹⁶, Jørgen F P Wojtaszewski¹⁴, Martin Whitham¹⁷, Mark A Febbraio¹⁸

Affiliations

¹ Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo 0317, Norway; Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
² Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC 3052, Australia.
³ Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC 3052, Australia; Laboratory of Neuromuscular Adaptations to Strength Training, School of Physical Education and Sport, University of São Paulo (USP), São Paulo 05508-030, Brazil; Center of Study in Exercise and Oncology (CEEO), Campinas 13083-888, Brazil.
⁴ Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; School of Dentistry & Medical Sciences, Charles Sturt University, Wagga Wagga, NSW 2678, Australia.
⁵ School of Biomedical Engineering, University of Technology, Sydney, NSW 2678, Australia.
⁶ College of Medicine, University of Oklahoma, Oklahoma City, OK 73117, USA; Institute of Molecular Biosciences, University of Queensland, St. Lucia, QLD 4072, Australia.
⁷ Institute of Molecular Biosciences, University of Queensland, St. Lucia, QLD 4072, Australia.
⁸ Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
⁹ CSIRO Manufacturing, Clayton, VIC 3168, Australia.
¹⁰ Australian Proteome Analysis Facility, Macquarie University, Sydney, NSW 2109, Australia; School of Medical Sciences, University of Sydney, Sydney, NSW 2050, Australia.
¹¹ Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC 3053, Australia; Department of Physiology, The University of Melbourne, Melbourne, VIC 3052, Australia.
¹² Department of Physiology, The University of Melbourne, Melbourne, VIC 3052, Australia.
¹³ Copenhagen University Hospital, Copenhagen 2100, Denmark.
¹⁴ Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen 2100, Denmark.
¹⁵ Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19144, USA.
¹⁶ Baker Heart and Diabetes Institute, Prahran, VIC 3004, Australia.
¹⁷ School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Edgbaston B15 2TT, UK. Electronic address: M.Whitham@bham.ac.uk.
¹⁸ Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC 3052, Australia. Electronic address: mark.febbraio@monash.edu.

PMID: 39341495
DOI: 10.1016/j.jshs.2024.100991

Abstract

Background: Regular exercise can reduce incidence and progression of breast cancer, but the mechanisms for such effects are not fully understood.

Methods: We used a variety of rodent and human experimental model systems to determine whether exercise training can reduce tumor burden in breast cancer and to identify mechanism associated with any exercise training effects on tumor burden.

Results: We show that voluntary wheel running slows tumor development in the mammary specific polyomavirus middle T antigen overexpression (MMTV-PyMT) mouse model of breast cancer but only when mice are not housed alone. We identify the proteoglycan decorin as a contraction-induced secretory factor that systemically increases in patients with breast cancer immediately following exercise. Moreover, high expression of decorin in tumors is associated with improved prognosis in patients, while treatment of breast cancer cells in vitro with decorin reduces cell proliferation. Notwithstanding, when we overexpressed decorin in murine muscle or injected recombinant decorin systemically into mouse models of breast cancer, elevated plasma decorin concentrations did not result in higher tumor decorin levels and tumor burden was not improved.

Conclusion: Exercise training is anti-tumorigenic in a mouse model of luminal breast cancer, but the effect is abrogated by social isolation. The proteoglycan decorin is an exercise-induced secretory protein, and tumor decorin levels are positively associated with improved prognosis in patients. The hypothesis that elevated plasma decorin is a mechanism by which exercise training improves breast cancer progression in humans is not, however, supported by our pre-clinical data since elevated circulating decorin did not increase tumor decorin levels in these models.

Keywords: Breast cancer; Exercise training; Muscle secretory factors; Proteoglycans.