Oxytocin mediates the beneficial effects of the exercise training on breast cancer

Abstract

What is the central question of this study? We hypothesized that potential anti-tumour effects of exercise training might be mediated by oxytocin and explored the underlying mechanisms in a mouse model of breast cancer. What is the main finding and its importance? Interval exercise training, by inducing oxytocin secretion, may reduce the activity of the PI3K/Akt and ERK pathways, and consequently, results in a smaller tumour volume in a mouse model of breast cancer. Exercise training can affect the growth of breast tumours. We hypothesized that exercise training might reduce breast tumour growth by inducing oxytocin (OT) secretion and its related signalling pathways, such as PI3K/Akt and ERK. Therefore, 56 BALB/c mice were equally divided into seven groups to study the effects of OT and atosiban (an oxytocin receptor antagonist) together with interval exercise training on mammary tumour growth, as well as tumour-related signalling pathways, including PI3K/Akt and ERK. Animal weight, OT plasma concentration, tumour weight and volume were measured at the end of the study. PI3K/Akt and ERK were evaluated by Western blot and qPCR assays. The results showed that OT plasma concentration was significantly increased in trained animals. The volume and weight of tumours were decreased significantly after both exercise training and OT administration. The expression of genes involved in tumour cell proliferation, such as PI3KR2, Akt and mTOR, was notably lower in the exercise-trained and OT-treated groups. Furthermore, the expression of genes involved in cell apoptosis, such as caspase-3 and Bax, was significantly increased in the tumour tissues. In addition, Western blot results showed that phosphorylated Akt and ERK were significantly decreased in the exercise training and OT groups compared with the tumour group. Interestingly, atosiban reversed these effects. These results indicated that interval exercise training, acting via OT secretion, may reduce PI3K/Akt and ERK axis activities, and consequently, decrease tumour volume and weight in a mouse model of breast cancer.

The oxytocin receptor signalling system and breast cancer: a critical review

“…A mouse xenograft model study demonstrated that OT can mediate the beneficial effects of physical exercise on breast cancer growth. Both exercise and OT administration decreased tumour volume and weight, and OT plasma concentration in the tumour and exercise group was more than 10-fold higher than in the tumour control group (tumour without exercise) [56]. OT levels in the pituitary and blood also increased in a rat breast cancer model induced by N-methyl-nitrosourea (NMU)-treatment due to inhibition of insulin-regulated aminopeptidase (an oxytocinase) and decrease of catabolism of OT in the hypothalamus [57].…”

“…Meanwhile, inhibition of PLC with its inhibitor U73122 also abolished the inhibition of cell growth by OTR coupling to Gα i , which is possibly a result of PLC activation by the βγ complexes released by Gα i [115]. The Gα i pathway appears to also mediate breast cancer growth inhibitory effects of OT, with the involvement of the PI3K/Akt pathway [56,97]. In MCF-7 cells, which express OTR and feature a PI3K activating mutation, a 30 min incubation with OT (125-1,000 nM) reduced the abundance of PI3K signalling components, including a reduction of PI3K p85, PI3K p110, and pAktS 473 , and Akt phosphorylation downstream of OTR requires Gα i and a structural change in the receptor [116].…”

“…AT used to be considered an OTR antagonist, but was later characterised as a biased OTR ligand that blocks the Gα q/11 pathway and activates the Gα i3 pathway [98,99]. By contrast, AT had no effects on tumour reduction in the mouse MC4-L2 carcinoma models, where OT reduced tumour growth [56,97]. 111 In-labelled OT-like tracer 111 In-DOTA-LVT ( 111 In-1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid-Lys 8 -vasotocin) [100], and its improved version 111 In-DOTA-dLVT ( 111 In-1,4,7,10-tetraazacyclododecane-N,N', N",N"'-tetraacetic acid-Lys 8 -deamino-vasotocin) [101] were developed to visualise OTR-expressing breast tumours and to study tracer/ligand uptake in mouse xenograft No exact number shown, calculated according to data or figure of publication.…”

Oxytocin and cancer: An emerging link

“…Importantly, anti-proliferative and tumor inhibitory properties were also observed in vivo in both rat and mouse experimental models, and attributed to both oxytocin and its analogue F314[ 9 ]. Recently, it was suggested that exercise training, by inducing oxytocin secretion, may reduce the expression of specific signaling proteins involved in breast cancer[ 59 ].…”

“…The positive impact of exercise in blunting development of cancer and facilitating recovery may potentially be partly mediated through oxytocin. For example, oxytocin has been proposed to mediate an exercise-induced reduction in the expression of specific signaling molecules involved in breast cancer[ 59 ]. It has also recently been shown in vivo that the combination of exogenous oxytocin with exercise improves cardiac function, which might be associated with improved cancer survival.…”