title: Poor early growth and excessive adult calorie intake independently and additively affect mitogenic signaling and increase mammary tumor susceptibility.
abstract: We previously showed that offspring of rat dams receiving a protein-restricted (low protein) diet throughout pregnancy and lactation develop mammary tumors more quickly. Rapid post-weaning mammary growth and mammary tissue overexpression of insulin receptor, insulin-like growth factor-1 receptor (IGF-1R), estrogen receptor isoform alpha and v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2), correlated with this risk. The objectives of this study were therefore (i) to identify underlying mechanisms of increased risk through candidate and global approaches; (ii) to determine if excessive calorie intake further increased risk and if so, (iii) to identify the molecular mechanisms mediating this. We provide evidence for transcriptional upregulation of IGF-1R by Sp1 in LP mammary tissue (P < 0.01). Cell cycle control and DNA damage repair gene cyclin-dependent kinase inhibitor 1A (CDKN1A) (p21waf1) was also upregulated (P < 0.05) as was transcription factor nuclear factor of kappa light polypeptide gene enhancer in B-cell (P < 0.05) and adhesion gene CDH1 (P < 0.05). Invasion and metastasis markers matrix metalloproteinase 9 and serpin peptidase inhibitor, clade E, member 1 (SERPIN1) were upregulated (both P < 0.05), whereas metastasis suppressor gene NME1 was downregulated (P < 0.01). Feeding a highly palatable diet (HPD) to increase calorie intake from puberty, additively and independently increased early mammary tumor risk, which correlated with increased serum insulin and triglyceride concentrations (P < 0.05). PTEN gene expression was reduced both by early protein restriction (P < 0.05) and HPD (P < 0.01), which may induce Akt in cell survival pathways. Progesterone receptor and ERBB2 (both P < 0.05) expression increased as an effect of an interaction between maternal diet and adult nutrition, with subsequent downstream activation of the mitogen-activated protein kinase pathway. We conclude that poor early growth and excessive calorie intake exert independent and additive effects on mitogenic growth factor signaling to influence mammary tumor susceptibility.
authors.affiliation: Department of Clinical Biochemistry, University of Cambridge, Metabolic Research Laboratories, Institute of Metabolic Science, Level 4, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK. df220@cam.ac.uk
authors.forename: D S
authors.initials: DS
authors.lastname: Fernandez-Twinn
authors.forename: S
authors.initials: S
authors.lastname: Ekizoglou
authors.forename: M S
authors.initials: MS
authors.lastname: Martin-Gronert
authors.forename: J
authors.initials: J
authors.lastname: Tarry-Adkins
authors.forename: A P
authors.initials: AP
authors.lastname: Wayman
authors.forename: M J
authors.initials: MJ
authors.lastname: Warner
authors.forename: J-A
authors.initials: JA
authors.lastname: Luan
authors.forename: B A
authors.initials: BA
authors.lastname: Gusterson
authors.forename: S E
authors.initials: SE
authors.lastname: Ozanne
mesh_terms: D000818:Animals; D001835:Body Weight; D004198:Disease Susceptibility; D002149:Energy Intake; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006130:Growth Disorders / Q000150:complications*; D008321:Mammary Glands, Animal / Q000737:chemistry / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000209:etiology*; D051381:Rats; D017208:Rats, Wistar; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000502:physiology; D017526:Receptor, IGF Type 1 / Q000032:analysis / Q000235:genetics; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000032:analysis / Q000235:genetics
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D017526:Receptor, IGF Type 1; D016329:Sp1 Transcription Factor; C483804:Erbb2 protein, rat