Excessive Weight Gain during Pregnancy Increases Carcinogen-Induced Mammary Tumorigenesis in Sprague-Dawley and Lean and Obese Zucker Rats

Abstract

Excessive weight gain during pregnancy increases breast cancer risk in women. To determine whether this may be caused by increased pregnancy leptin levels, leptin receptor (Ob-Rb) mutant (fa/fa) and wild-type (FA/FA) female Zucker rats and Sprague-Dawley rats were fed during pregnancy an obesity-inducing high-fat diet (OID) that increased pregnancy weight gain, or a control diet. Because mutant Zucker rats do not readily become pregnant, their pregnancy was mimicked by exposing the rats to subcutaneous silastic capsules containing 150 microg of estradiol and 30 mg of progesterone for 3 wk. Sprague-Dawley rats underwent normal pregnancy. An assessment of hormone levels on gestation d 17 indicated that an exposure to the OID significantly elevated serum leptin concentration but did not affect those of estradiol or insulin-like growth factor 1 (IGF-1). Insulin and adiponectin levels were higher in the obese than lean Zucker rats, but were not related to pregnancy weight gain. Exposure to the OID during pregnancy increased 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumorigenesis in all genetic backgrounds, including leptin receptor mutant Zucker rats. The results also indicated that obese Zucker rats that underwent mimicked pregnancy developed more palpable tumors and hyperplastic alveolar nodules that lean Zucker rats. Further, mammary epithelial cell proliferation assessed using PCNA staining was elevated in obese Zucker rats as was activation of mitogen-activated protein kinase (MAPK); however, neither of these 2 changes occurred in the context of excessive weight gain during pregnancy. It remains to be determined whether an increase in leptin levels was causally associated with an increase in the dams' mammary tumorigenesis, including in obese Zucker rats with dramatically reduced leptin signaling.

Insulin Exerts Direct Effects on Carcinogenic Transformation of Human Endometrial Organotypic Cultures

“…This appears to be downstream of MAPK, and not PI3K/AKT signaling, because AKT phosphorylation was inconsistently induced in repetitions of this experiment ( Figure 5). DMBA has been shown to both induce and decrease MAPK levels and signaling in animal carcinogenesis models (22)(23)(24)(25)(26)(27). Variables shown to be associated with these disparate results are mutations that arise during tumorigenesis.…”

Female heterozygous (+/<i>fa</i>) Zucker rats as a novel leptin-related mammary carcinogenesis model

“…In contrast, lean Zucker (+/fa or +/+) rats show almost normal metabolic functions, and have been used as controls in various types of physiochemical and pathological experiments (Bray, 1977). The Zucker rat has been recognized as a superior model to investigate effects of obesity on chronic disease development, including cancer (Bray, 1977;de Assis et al, 2006;Hakkak et al, 2007), but its utility for investigations of mammary carcinogenesis is limited due to scant epithelial development in mature mammary glands of obese as compared with lean counterparts (Hu et al, 2002). Since it was reported that young heterozygous lean Zucker (+/fa) rats demonstrate a number of differences from wild type lean Zucker (+/+) rats, e.g., higher body weights, fat cell size, inguinal fat pad weights, pad-to-body weight ratios, serum cholesterol, adipose tissue lipoprotein lipase and glycerol-3-phosphate dehydrogenase, hepatic and adipose tissue 6-phosphogluconate dehydrogenase activities and serum leptin levels (1.6 and 0.9 ng/ml in +/fa and +/+, respectively, ) Heo et al, 2002;Phillips and Cleary, 1994;Truett et al, 1995;Zhang et al, 1997), we here investigated whether they might provide the basis for a leptin-related mammary carcinogenesis model.…”

Pregnancy hormonal environment and mother’s breast cancer risk

“…The latter express defective leptin receptors (Ob-R), which cause them to become morbidly obese, particularly when fed high-fat diet [52] . In all three models, consumption of OID and excessive weight gain during pregnancy increased dams ' later mammary tumorigenesis [53] . However, neither E2 nor IGF-1 levels were associated with excessive weight gain during pregnancy, but leptin was.…”

“…However, as discussed below, there is some evidence that mothers with the highest range of estrogens during pregnancy are at elevated breast cancer risk [51,52] . Furthermore, elevated pregnancy leptin [53] , and perhaps IGF-1 levels, may increase mothers ' later breast cancer risk.…”