Hjorth Marit, Egan Casey L, Telles Guilherme D, Pal Martin, Gallego-Ortega David, Fuller Oliver K, McLennan Emma D, Gillis Ryan D, Oh Tae Gyu, Muscat George E O, Tegegne Surafel, Mah Michael S M, Skhinas Joanna, Estevez Emma, Adams Timothy E, McKay Matthew J, Molloy Mark, Watt Kevin I, Qian Hongwei, Gregorevic Paul, Cox Thomas R, Hojman Pernille, Midtgaard Julie, Christensen Jesper F, Friedrichsen Martin, Iozzo Renato V, Sloan Erica K, Drew Brian G, Wojtaszewski Jørgen F P, Whitham Martin, Febbraio Mark A
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.
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC 3052, Australia.
J Sport Health Sci. 2024 Sep 26;14:100991. doi: 10.1016/j.jshs.2024.100991.
Regular exercise can reduce incidence and progression of breast cancer, but the mechanisms for such effects are not fully understood. The purpose of this study was to examine the mechanisms behind the protective effects of exercise.
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.
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.
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.
规律运动可降低乳腺癌的发病率和进展，但此类作用的机制尚未完全明确。本研究的目的是探究运动产生保护作用的背后机制。
我们使用了多种啮齿动物和人类实验模型系统，以确定运动训练是否能减轻乳腺癌的肿瘤负担，并确定与运动训练对肿瘤负担产生的任何影响相关的机制。
我们发现，在乳腺癌的乳腺特异性多瘤病毒中T抗原过表达（MMTV-PyMT）小鼠模型中，自愿轮转跑步可减缓肿瘤发展，但仅在小鼠不单独饲养时有效。我们确定蛋白聚糖核心蛋白聚糖是一种收缩诱导的分泌因子，乳腺癌患者在运动后其在体内会系统性增加。此外，肿瘤中核心蛋白聚糖的高表达与患者预后改善相关，而在体外使用核心蛋白聚糖处理乳腺癌细胞可降低细胞增殖。尽管如此，当我们在小鼠肌肉中过表达核心蛋白聚糖或向乳腺癌小鼠模型全身注射重组核心蛋白聚糖时，血浆核心蛋白聚糖浓度升高并未导致肿瘤核心蛋白聚糖水平升高，肿瘤负担也未得到改善。
运动训练在管腔型乳腺癌小鼠模型中具有抗肿瘤作用，但这种作用会因社会隔离而消除。蛋白聚糖核心蛋白聚糖是一种运动诱导的分泌蛋白，肿瘤核心蛋白聚糖水平与患者预后改善呈正相关。然而，我们的临床前数据并不支持血浆核心蛋白聚糖升高是运动训练改善人类乳腺癌进展的一种机制这一假设，因为在这些模型中循环核心蛋白聚糖升高并未增加肿瘤核心蛋白聚糖水平。
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