title: Mammary gland density predicts the cancer inhibitory activity of the N-3 to N-6 ratio of dietary fat.
abstract: This study investigated the effect of a broad range of dietary ratios of n-3:n-6 fatty acids on mammary gland density and mammary cancer risk. Cancer was induced in female rats by N-methyl-N-nitrosourea. Purified diet that provided 30% of dietary kilocalories from fat was formulated to contain ratios of n-3:n-6 fatty acids from 25:1 to 1:25. Mammary gland density was determined by digital analysis, fatty acids by gas chromatography/flame ionization detection, and other plasma analytes via ELISA. Mammary gland density was reduced dose dependently at n-3:n-6 ratios from 1:1 to 25:1 (r = -0.477, P = 0.038), with a 20.3% decrease of mammary gland density between n-3:n-6 of 1:1 versus 25:1, P < 0.001. Mammary carcinogenesis was inhibited in the absence or presence of tamoxifen (1 mg/kg diet) in a manner predicted by mammary gland density. Plasma n-3 fatty acid concentrations failed to increase above an n-3:n-6 ratio of 5:1, and changes in specific plasma n-3 or n-6 fatty acids were not predictive of mammary gland density or cancer inhibitory activity. A strong reciprocal effect of the n-3:n-6 ratio on plasma leptin (decreased, P = 0.005) and adiponectin (increased, P < 0.001) was observed indicating adipose tissue function was modulated. However, neither cytokine was predictive of mammary gland density. Plasma insulin-like growth factor I (IGF-I) decreased with increasing dietary n-3:n-6 ratio (P = 0.004) and was predictive of the changes in mammary gland density (r = 0.362, P < 0.005). These findings indicate that (i) mammary gland density predicted the carcinogenic response, (ii) the n-3:n-6 ratio exerts effects in the presence or absence of hormonal regulation of carcinogenesis, and (iii) signaling pathways regulated by IGF-I are potential targets for further mechanistic investigation.
authors.affiliation: Cancer Prevention Laboratory, Colorado State University, Fort Collins, 80523, USA.
authors.forename: Zongjian
authors.initials: Z
authors.lastname: Zhu
authors.forename: Weiqin
authors.initials: W
authors.lastname: Jiang
authors.forename: John N
authors.initials: JN
authors.lastname: McGinley
authors.forename: Bogden
authors.initials: B
authors.lastname: Prokopczyk
authors.forename: John P
authors.initials: JP
authors.lastname: Richie
authors.forename: Karam
authors.initials: K
authors.lastname: El Bayoumy
authors.forename: Andrea
authors.initials: A
authors.lastname: Manni
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Thompson
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D016207:Cytokines / Q000097:blood; D004032:Diet; D004797:Enzyme-Linked Immunosorbent Assay; D015525:Fatty Acids, Omega-3 / Q000378:metabolism*; D043371:Fatty Acids, Omega-6 / Q000378:metabolism*; D005260:Female; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000187:drug effects* / Q000473:pathology*; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D008770:Methylnitrosourea / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D000477:Alkylating Agents; D018931:Antineoplastic Agents, Hormonal; D016207:Cytokines; D015525:Fatty Acids, Omega-3; D043371:Fatty Acids, Omega-6; D013629:Tamoxifen; D007334:Insulin-Like Growth Factor I; D008770:Methylnitrosourea