Tumor Phenotype and Gene Expression During Early Mammary Tumor Development in Offspring Exposed to Alcohol In Utero

Catina Crismale-Gann, Hillary Stires, Tiffany A. Katz, Wendie S. Cohick

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Background: Alcohol exposure in utero increases susceptibility to carcinogen-induced mammary tumorigenesis in adult offspring and causes tumors with a more malignant phenotype. This study was conducted to identify changes early in tumor development that might lead to this outcome. Methods: Pregnant Sprague–Dawley rats were fed a liquid diet containing 6.7% ethanol (alcohol), an isocaloric liquid diet without alcohol (pair-fed), or rat chow ad libitum (ad lib) from gestation day 7 until parturition. At birth, female progeny were cross-fostered to control dams. Pups were weaned at postnatal day (PND) 21 and fed rat chow ad libitum for the remainder of the experiment. Female offspring were administered N-nitroso-N-methylurea (NMU; 50 mg/kg body weight) on PND 50. Mammary glands were palpated weekly, and offspring were euthanized at 16 weeks post-NMU injection. Results: At 16 weeks post-NMU, tumor multiplicity was greater in alcohol-exposed offspring compared with control groups. Estrogen receptor-α (ER) mRNA expression was decreased in tumors from alcohol-exposed offspring, and these animals developed more ER-negative tumors relative to the pair-fed group. Alcohol-exposed offspring also tended to develop more progesterone receptor (PR)-positive tumors. All tumors were HER2-negative. PR positivity was associated with higher Ki67 expression, suggesting that PR-positive tumors were more proliferative. Tumors from alcohol-exposed animals exhibited increased mRNA expression of the insulin-like growth factor (IGF) family members IGF-II and IGFBP-5. IGF-II and DNA methyltransferase mRNA tended to be greater in the normal contralateral mammary glands of these animals. Conclusions: These data indicate that alcohol exposure in utero may shift NMU-induced tumor development toward a more aggressive phenotype and that alterations in IGF-II expression may contribute to these changes. Additional studies should be aimed at epigenetic mechanisms that underlie IGF-II expression to further delineate how this gene is altered in mammary glands of adults exposed to alcohol in utero.

Original languageEnglish (US)
Pages (from-to)1679-1690
Number of pages12
JournalAlcoholism: Clinical and Experimental Research
Volume40
Issue number8
DOIs
StatePublished - Aug 1 2016

All Science Journal Classification (ASJC) codes

  • Medicine (miscellaneous)
  • Toxicology
  • Psychiatry and Mental health

Keywords

  • Alcohol Exposure In Utero
  • Hormone Receptors
  • Insulin-Like Growth Factor
  • Mammary Tumor
  • Tumor Phenotype

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