Maternal obesogenic diet induces endometrial hyperplasia, an early hallmark of endometrial cancer, in a diethylstilbestrol mouse model.

Theresa O Owuor,Lauren Reschke,Zeel Modi,Michaela Reid,Ian Hagemann,Suellen Greco,Kelle H Moley

doi:10.1371/journal.pone.0186390

Abstract

Thirty-eight percent of US adult women are obese, meaning that more children are now born of overweight and obese mothers, leading to an increase in predisposition to several adult onset diseases. To explore this phenomenon, we developed a maternal obesity animal model by feeding mice a diet composed of high fat/ high sugar (HF/HS) and assessed both maternal diet and offspring diet on the development of endometrial cancer (ECa). We show that maternal diet by itself did not lead to ECa initiation in wildtype offspring of the C57Bl/6J mouse strain. While offspring fed a HF/HS post-weaning diet resulted in poor metabolic health and decreased uterine weight (regardless of maternal diet), it did not lead to ECa. We also investigated the effects of the maternal obesogenic diet on ECa development in a Diethylstilbestrol (DES) carcinogenesis mouse model. All mice injected with DES had reproductive tract lesions including decreased number of glands, condensed and hyalinized endometrial stroma, and fibrosis and increased collagen deposition that in some mice extended into the myometrium resulting in extensive disruption and loss of the inner and outer muscular layers. Fifty percent of DES mice that were exposed to maternal HF/HS diet developed several features indicative of the initial stages of carcinogenesis including focal glandular and atypical endometrial hyperplasia versus 0% of their Chow counterparts. There was an increase in phospho-Akt expression in DES mice exposed to maternal HF/HS diet, a regulator of persistent proliferation in the endometrium, and no difference in total Akt, phospho-PTEN and total PTEN expression. In summary, maternal HF/HS diet exposure induces endometrial hyperplasia and other precancerous phenotypes in mice treated with DES. This study suggests that maternal obesity alone is not sufficient for the development of ECa, but has an additive effect in the presence of a secondary insult such as DES.

Highlights

Endometrial cancer (ECa) is the most common of all gynecological cancers and the fourth most common cancer in women in the United States[1]
Our lab has previously demonstrated that maternal obesity in mice caused by exposure to a high fat/ high sugar (HF/HS) diet prior to conception, during pregnancy, and throughout lactation impairs early embryo and gamete development and increases male offspring’s risk of prostate hyperplasia[20, 45]
We sought to investigate the developmental origins of ECa using a maternal HF/HS diet mouse model

Summary

Introduction

Endometrial cancer (ECa) is the most common of all gynecological cancers and the fourth most common cancer in women in the United States[1]. Several factors including exposure to unopposed high estrogen levels, family history, age, radiation therapy, mutations, and obesity, have been linked to an increased risk of ECa[3]. Several epidemiological studies have associated an increased risk of ECa with weight gain during adulthood[5,6,7]. Adult weight gain was more strongly associated with type I endometrial cancer than type II[5]. (2) Second, obese women have an increased production of adipokines, namely leptin and adiponectin, from adipose tissue which has been shown to stimulate cancer cells, be involved in angiogenesis, cell apoptosis, cell invasiveness, and create a pro-inflammatory state via production of cytokines such as Interleukins 6 and 12, and Tumor necrosis factor alpha [9]. The link between ECa and obesity is still unclear, but three possible mechanisms have been proposed: (1) First, obese women have a higher level of circulating estrogen as a result of the peripheral conversion of androgen in adipose tissue to estrogen such as estradiol and estrone[8]. (2) Second, obese women have an increased production of adipokines, namely leptin and adiponectin, from adipose tissue which has been shown to stimulate cancer cells, be involved in angiogenesis, cell apoptosis, cell invasiveness, and create a pro-inflammatory state via production of cytokines such as Interleukins 6 and 12, and Tumor necrosis factor alpha [9]. (3) Third, obesity leads to the development of hyperinsulinemia resulting from chronic insulin resistance, which has been associated with complex molecular changes and interactions that favor tumor formation [10, 11]

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