TY - JOUR
T1 - Social isolation induces autophagy in the mouse mammary gland
T2 - Link to increased mammary cancer risk
AU - Sumis, Allison
AU - Cook, Katherine L.
AU - Andrade, Fabia O.
AU - Hu, Rong
AU - Kidney, Emma
AU - Zhang, Xiyuan
AU - Kim, Dominic
AU - Carney, Elissa
AU - Nguyen, Nguyen
AU - Yu, Wei
AU - Bouker, Kerrie B.
AU - Cruz, Idalia
AU - Clarke, Robert
AU - Hilakivi-Clarke, Leena
N1 - Publisher Copyright:
© 2016 Society for Endocrinology Printed in Great Britain.
PY - 2016/10
Y1 - 2016/10
N2 - Social isolation is a strong predictor of early all-cause mortality and consistently increases breast cancer risk in both women and animal models. Because social isolation increases body weight, we compared its effects to those caused by a consumption of obesity-inducing diet (OID) in C57BL/6 mice. Social isolation and OID impaired insulin and glucose sensitivity. In socially isolated, OID-fed mice (I-OID), insulin resistance was linked to reduced Pparg expression and increased neuropeptide Y levels, but in group-housed OID fed mice (G-OID), it was linked to increased leptin and reduced adiponectin levels, indicating that the pathways leading to insulin resistance are different. Carcinogeninduced mammary tumorigenesis was significantly higher in I-OID mice than in the other groups, but cancer risk was also increased in socially isolated, control diet-fed mice (I-C) and G-OID mice compared with that in controls. Unfolded protein response (UPR) signaling (GRP78; IRE1) was upregulated in the mammary glands of OID-fed mice, but not in control diet-fed, socially isolated I-C mice. In contrast, expression of BECLIN1, ATG7 and LC3II were increased, and p62 was downregulated by social isolation, indicating increased autophagy. In the mammary glands of socially isolated mice, but not in G-OID mice, mRNA expressions of p53 and the p53-regulated autophagy inducer Dram1 were upregulated, and nuclear p53 staining was strong. Our findings further indicated that autophagy and tumorigenesis were not increased in Atg7+/- mice kept in social isolation and fed OID. Thus, social isolation may increase breast cancer risk by inducing autophagy, independent of changes in body weight.
AB - Social isolation is a strong predictor of early all-cause mortality and consistently increases breast cancer risk in both women and animal models. Because social isolation increases body weight, we compared its effects to those caused by a consumption of obesity-inducing diet (OID) in C57BL/6 mice. Social isolation and OID impaired insulin and glucose sensitivity. In socially isolated, OID-fed mice (I-OID), insulin resistance was linked to reduced Pparg expression and increased neuropeptide Y levels, but in group-housed OID fed mice (G-OID), it was linked to increased leptin and reduced adiponectin levels, indicating that the pathways leading to insulin resistance are different. Carcinogeninduced mammary tumorigenesis was significantly higher in I-OID mice than in the other groups, but cancer risk was also increased in socially isolated, control diet-fed mice (I-C) and G-OID mice compared with that in controls. Unfolded protein response (UPR) signaling (GRP78; IRE1) was upregulated in the mammary glands of OID-fed mice, but not in control diet-fed, socially isolated I-C mice. In contrast, expression of BECLIN1, ATG7 and LC3II were increased, and p62 was downregulated by social isolation, indicating increased autophagy. In the mammary glands of socially isolated mice, but not in G-OID mice, mRNA expressions of p53 and the p53-regulated autophagy inducer Dram1 were upregulated, and nuclear p53 staining was strong. Our findings further indicated that autophagy and tumorigenesis were not increased in Atg7+/- mice kept in social isolation and fed OID. Thus, social isolation may increase breast cancer risk by inducing autophagy, independent of changes in body weight.
KW - Autophagy
KW - Breast cancer
KW - Social isolation
UR - http://www.scopus.com/inward/record.url?scp=84993945253&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84993945253&partnerID=8YFLogxK
U2 - 10.1530/ERC-16-0359
DO - 10.1530/ERC-16-0359
M3 - Article
C2 - 27550962
AN - SCOPUS:84993945253
SN - 1351-0088
VL - 23
SP - 839
EP - 856
JO - Endocrine-related cancer
JF - Endocrine-related cancer
IS - 10
ER -