title: Social isolation induces autophagy in the mouse mammary gland: link to increased mammary cancer risk.
abstract: 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. Carcinogen-induced 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.
authors.affiliation: Department of OncologyGeorgetown University, Washington, District of Columbia, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Sumis
authors.affiliation: Department of OncologyGeorgetown University, Washington, District of Columbia, USA Department of SurgeryWake Forest University, Winston-Salem, North Carolina, USA.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Cook
authors.affiliation: Department of OncologyGeorgetown University, Washington, District of Columbia, USA Faculty of Pharmaceutical SciencesDepartment of Food and Experimental Nutrition, University of São Paulo, São Paulo, Brazil.
authors.forename: Fabia O
authors.initials: FO
authors.lastname: Andrade
authors.affiliation: Department of OncologyGeorgetown University, Washington, District of Columbia, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Hu
authors.affiliation: Department of OncologyGeorgetown University, Washington, District of Columbia, USA.
authors.forename: Emma
authors.initials: E
authors.lastname: Kidney
authors.affiliation: Department of OncologyGeorgetown University, Washington, District of Columbia, USA.
authors.forename: Xiyuan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of OncologyGeorgetown University, Washington, District of Columbia, USA.
authors.forename: Dominic
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of OncologyGeorgetown University, Washington, District of Columbia, USA.
authors.forename: Elissa
authors.initials: E
authors.lastname: Carney
authors.affiliation: Department of OncologyGeorgetown University, Washington, District of Columbia, USA.
authors.forename: Nguyen
authors.initials: N
authors.lastname: Nguyen
authors.affiliation: Department of OncologyGeorgetown University, Washington, District of Columbia, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Yu
authors.affiliation: Department of OncologyGeorgetown University, Washington, District of Columbia, USA.
authors.forename: Kerrie B
authors.initials: KB
authors.lastname: Bouker
authors.affiliation: Department of OncologyGeorgetown University, Washington, District of Columbia, USA.
authors.forename: Idalia
authors.initials: I
authors.lastname: Cruz
authors.affiliation: Department of OncologyGeorgetown University, Washington, District of Columbia, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Clarke
authors.affiliation: Department of OncologyGeorgetown University, Washington, District of Columbia, USA clarkel@georgetown.edu.
authors.forename: Leena
authors.initials: L
authors.lastname: Hilakivi-Clarke
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D000071193:Autophagy-Related Protein 7 / Q000235:genetics*; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology; D004032:Diet; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D008321:Mammary Glands, Animal / Q000473:pathology*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology* / Q000523:psychology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008820:Mice, Obese; D008822:Mice, Transgenic; D009765:Obesity / Q000150:complications / Q000473:pathology; D012307:Risk Factors; D012934:Social Isolation; D013315:Stress, Psychological / Q000150:complications / Q000235:genetics / Q000473:pathology
chemical_list: C502661:Atg7 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D000071193:Autophagy-Related Protein 7
keywords: autophagy; breast cancer; social isolation