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Tumor Phenotype and Gene Expression During Early Mammary Tumor Development in Offspring Exposed to Alcohol In Utero
Author(s) -
CrismaleGann Catina,
Stires Hillary,
Katz Tiffany A.,
Cohick Wendie S.
Publication year - 2016
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.13139
Subject(s) - offspring , endocrinology , medicine , in utero , biology , carcinogenesis , estrogen receptor , mammary gland , mammary tumor , carcinogen , pregnancy , fetus , cancer , breast cancer , genetics
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 HER 2‐negative. PR positivity was associated with higher Ki67 expression, suggesting that PR ‐positive tumors were more proliferative. Tumors from alcohol‐exposed animals exhibited increased m RNA expression of the insulin‐like growth factor ( IGF ) family members IGF ‐ II and IGFBP ‐5. IGF ‐ II and DNA methyltransferase m RNA 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.