| Poor early growth and excessive adult calorie intake independently and additively affect mitogenic signaling and increase mammary tumor susceptibility. | |
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MedLine Citation:
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PMID: 20460357 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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D S Fernandez-Twinn; S Ekizoglou; M S Martin-Gronert; J Tarry-Adkins; A P Wayman; M J Warner; J-A Luan; B A Gusterson; S E Ozanne |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-05-11 |
Journal Detail:
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Title: Carcinogenesis Volume: 31 ISSN: 1460-2180 ISO Abbreviation: Carcinogenesis Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-10-08 Completed Date: 2010-11-10 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8008055 Medline TA: Carcinogenesis Country: England |
Other Details:
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Languages: eng Pagination: 1873-81 Citation Subset: IM |
Affiliation:
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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 |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Body Weight Disease Susceptibility Energy Intake* Extracellular Signal-Regulated MAP Kinases / metabolism Female Gene Expression Profiling Growth Disorders / complications* Mammary Glands, Animal / chemistry, metabolism Mammary Neoplasms, Animal / etiology* Rats Rats, Wistar Receptor, IGF Type 1 / analysis, genetics Receptor, erbB-2 / genetics, physiology Signal Transduction* Sp1 Transcription Factor / analysis, genetics |
| Chemical | |
Reg. No./Substance:
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0/Erbb2 protein, rat; 0/Sp1 Transcription Factor; EC 2.7.10.1/Receptor, IGF Type 1; EC 2.7.10.1/Receptor, erbB-2; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases |
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