High birth weight increases mammary tumorigenesis in rats

Abstract

Epidemiological studies have investigated whether a high birth weight is associated with increased breast cancer risk, but the results remain inconclusive. This study was designed to determine whether high birth weight increases later susceptibility to carcinogen-induced mammary tumorigenesis in an animal model and to determine mechanisms mediating this association. Pregnant female Sprague Dawley rats were fed either a control or a high-fat diet during the extent of gestation. Maternal exposure to the highfat diet increased pregnancy leptin levels and offspring's birth weight, but had no effect on pregnancy estradiol or insulin-like growth factor 1 levels. Changes in the offspring's mammary gland morphology and protein expression were assessed. The mammary epithelial tree of the high-birth-weight offspring was denser, contained more terminal end buds and exhibited higher number of proliferating cells. Further, their mammary glands expressed lower levels of ER-a, but higher levels of activated MAPK. No alterations in apoptosis were noted. High-birth-weight rats developed 7,12-dimethylbenz[a]anthracene-induced mammary tumors significantly earlier, and tumors grew larger than in the controls. The tumors in this group expressed higher levels of leptin receptor and activated Akt, and contained fewer apoptotic cells than those in the controls. Our results indicate that high birth weight is related to shortened latency to develop mammary tumors-perhaps reflecting an increase in activated MAPK levels and increased tumor growth-perhaps caused by a lower apoptotic response due to higher leptin receptor and activated Akt levels in the tumors. ' 2006 Wiley-Liss, Inc.Key words: birth weight; breast cancer; animal model; leptinIn 1990, Dr. Trichopoulos proposed that some breast cancers originate already in utero as a consequence of high estrogenic environment.1 Since then, several human studies have addressed this hypothesis using different proxy measures of in utero estrogenic environment, including birth weight. Most epidemiological studies have reported that high birth weight increases a woman's breast cancer risk, 2-7 albeit some have not. 8The hypothesis that the in utero hormonal environment affects breast cancer risk can be tested more directly in animal models than in humans. Studies in rats have shown that an exposure to estradiol during pregnancy increases the female offspring's mammary tumorigenesis.9 How might this happen? One possibility is that high prenatal hormone levels alter the normal developmental programming of the mammary gland, causing changes in gland morphology and associated gene expression, most likely through epigenetic changes. In rats exposed to elevated levels of estradiol in utero, these morphological alterations are manifested as an increase in the number of terminal end buds (TEBs) 9,10 -structures that give rise to malignant mammary tumors 11 -and changes in the expression of genes that lead to increased cell proliferation and inhibition of apoptosis (Shajahan et al., unpublished data). The...

Birth weight and the risk of testicular cancer: A meta‐analysis

“…73,74 High birth weight has been associated with increased risk for childhood leukemia 75 and breast cancer 76 in epidemiologic and experimental studies. 77 As evident from previous studies, high birth weight may result from high levels of growth factors in utero, especially insulin and insulin-like growth factors I (IGF-I) and -II (IGF-II), which can increase the subsequent risk for cancer. [78][79][80][81] Gestational diabetes that is treated by dietary intervention only increases the risk of cryptorchidism.…”

Meeting Report on the 3rd International Congress on Developmental Origins of Health and Disease (DOHaD)

“…In a nonhuman primate model, chronic maternal overfeeding leads to fetal oxidative stress in the liver, resulting in fatty liver and disordered lipid handling (24). In a rat model, higher birth weight from maternal diet-induced obesity leads to mammary tumorigenesis (25).…”

“…While much attention has focused on the important and common outcomes of obesity, diabetes, and cardiovascular disease, the DOHaD principles apply as well to a range of conditions, including cancer, (25,(43)(44)(45)(46)(47)(48)(49) reproductive outcomes, (50,51) mental health and neurologic conditions, (52-57) and respiratory disease, (58 -61) as well 627 MEETING REPORT -3 rd DOHaD CONGRESS as body composition. A separate session reflected the primacy of the placenta not only in nutrient transport, but also as an endocrine organ and an important mediator of environmental cues itself (62)(63)(64)(65)(66).…”

Effects of Maternal Exposure to Cow's Milk High or Low in Isoflavones on Carcinogen-Induced Mammary Tumorigenesis among Rat Offspring

“…Human epidemiologic data suggest that high milk consumption during pregnancy is associated with increased birth weight (23), and a high birth weight has been linked to elevated maternal estrogen levels (24) and increased risk of later development of breast cancer (25). Consistent with the human data, mammary cancer risk is increased in rats which had a high birth weight (13).…”

“…For example, maternal exposure to a high-fat diet during pregnancy increases a female offspring's susceptibility to develop carcinogen-induced mammary tumors in rats (9,13), whereas whole wheat flour, containing lignans, and fish oil reduces the risk (10,12). The effects of maternal exposure to the isoflavone genistein during pregnancy on offspring's mammary tumorigenesis have also been intensively studied but results are conflicting (14).…”