Does Cancer Start in the Womb? Altered Mammary Gland Development and Predisposition to Breast Cancer due to in Utero Exposure to Endocrine Disruptors

Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA, USA.
Journal of Mammary Gland Biology and Neoplasia (Impact Factor: 4.53). 05/2013; 18(2). DOI: 10.1007/s10911-013-9293-5
Source: PubMed


We are now witnessing a resurgence of theories of development and carcinogenesis in which the environment is again being accepted as a major player in phenotype determination. Perturbations in the fetal environment predispose an individual to disease that only becomes apparent in adulthood. For example, gestational exposure to diethylstilbestrol resulted in clear cell carcinoma of the vagina and breast cancer. In this review the effects of the endocrine disruptor bisphenol-A (BPA) on mammary development and tumorigenesis in rodents is used as a paradigmatic example of how altered prenatal mammary development may lead to breast cancer in humans who are also widely exposed to it through plastic goods, food and drink packaging, and thermal paper receipts. Changes in the stroma and its extracellular matrix led to altered ductal morphogenesis. Additionally, gestational and lactational exposure to BPA increased the sensitivity of rats and mice to mammotropic hormones during puberty and beyond, thus suggesting a plausible explanation for the increased incidence of breast cancer.

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Available from: Cathrin Brisken, Sep 14, 2014
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    • "Extensive use of bisphenols caused increasing concern over the potential adverse effects provoked by these substances on human health (Song et al., 2014). The results of in vitro and in vivo studies as well as epidemiological surveys have demonstrated that BPA exhibits endocrine, hepatotoxic and neurotoxic potential and may increase risk of cancer development (Cabaton et al., 2006; Soto et al., 2013). Significantly less attention has been devoted BPA analogues including the effect of these substances on blood cells. "
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    ABSTRACT: Bisphenol A (BPA) has been shown to provoke many deleterious impacts on human health, and thus it is now successively substituted by BPA analogues, whose effects have been poorly investigated. Up to now, only one study has been realized to assess the effect of BPA on human erythrocytes, which showed its significant hemolytic and oxidative potential. Moreover, no study has been conducted to evaluate the effect of BPA analogues on red blood cells. The purpose of the present study was to compare the impact of BPA and its selected analogues such as bisphenol F (BPF), bisphenol S (BPS) and bisphenol AF (BPAF) on hemolytic and morphological changes and hemoglobin oxidation (methemoglobin formation) in human erythrocytes. The erythrocytes were incubated with different bisphenols concentrations ranging from 0.5 to 500 μg/ml for 1, 4 and 24 h. The compounds examined caused hemolysis in human erythrocytes with BPAF exhibiting the strongest effect. All bisphenols examined caused methemoglobin formation with BPA inducing the strongest oxidative potential. Flow cytometry analysis showed that all bisphenols (excluding BPS) induced significant changes in erythrocytes size. Changes in red blood cells shape were conducted using phase contrast microscopy. It was noticed that BPA and BPAF induced echinocytosis, BPF caused stomatocytosis, while BPS did not provoke changes in shape of red blood cells. Generally, the results showed that BPS, which is the main substituent of bisphenol A in polymers and thermal paper production, exhibited significantly lower disturbance of erythrocyte functions than BPA. Copyright © 2015. Published by Elsevier Inc.
    Comparative Biochemistry and Physiology Part C Toxicology & Pharmacology 07/2015; 176-177. DOI:10.1016/j.cbpc.2015.07.008 · 2.30 Impact Factor
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    • "One study concluded that somatic sequence variants in normal cell populations could be the earliest stage of oncogenesis [12]. Evidence that altered mammary gland development and predisposition to breast cancer is due to in utero exposure to endocrine disruptors has suggested that selection of cells with different phenotypic properties, presumably as a result of very early somatic mutations, may take place at the very earliest stages of breast tissue development [13]. Thus, we may need to reconsider whether accumulation of a critical number of oncogenic mutations, e.g., the buildup of driver somatic mutations, is the reason that many cancers occur later in life. "
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    ABSTRACT: Understanding genotype/phenotype relationships has become more complicated as increasing amounts of inter- and intra-tissue genetic heterogeneity have been revealed through next-generation sequencing and evidence showing that factors such as epigenetic modifications, non-coding RNAs and RNA editing can play an important role in determining phenotype. Such findings have challenged a number of classic genetic assumptions including (i) analysis of genomic sequence obtained from blood is an accurate reflection of the genotype responsible for phenotype expression in an individual; (ii) that significant genetic alterations will be found only in diseased individuals, in germline tissues in inherited diseases, or in specific diseased tissues in somatic diseases such as cancer; and (iii) that mutation rates in putative disease-associated genes solely determine disease phenotypes. With the breakdown of our traditional understanding of genotype to phenotype relationships, it is becoming increasingly apparent that new analytical tools will be required to determine the relationship between genotype and phenotypic expression. To this end, we are proposing that next-generation genetic database (NGDB) platforms be created that include new bioinformatics tools based on algorithms that can evaluate genetic heterogeneity, as well as powerful systems biology analysis tools to actively process and evaluate the vast amounts of both genomic and genomic-modifying information required to reveal the true relationships between genotype and phenotype.
    Human genomics 05/2014; 8(1):9. DOI:10.1186/1479-7364-8-9 · 2.15 Impact Factor
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    • "To clarify this process, several models have been used [5]–[8]. For instance, skin appendages including the mammary gland develop through complex reciprocal interactions between mesenchyme and epithelium [9], [10]. The latter is represented in the ducts of the breast, and the mesenchyme corresponds to the surrounding matrix and stromal cells. "
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    ABSTRACT: Mammary gland morphogenesis involves ductal elongation, branching, and budding. All of these processes are mediated by stroma - epithelium interactions. Biomechanical factors, such as matrix stiffness, have been established as important factors in these interactions. For example, epithelial cells fail to form normal acinar structures in vitro in 3D gels that exceed the stiffness of a normal mammary gland. Additionally, heterogeneity in the spatial distribution of acini and ducts within individual collagen gels suggests that local organization of the matrix may guide morphogenesis. Here, we quantified the effects of both bulk material stiffness and local collagen fiber arrangement on epithelial morphogenesis. The formation of ducts and acini from single cells and the reorganization of the collagen fiber network were quantified using time-lapse confocal microscopy. MCF10A cells organized the surrounding collagen fibers during the first twelve hours after seeding. Collagen fiber density and alignment relative to the epithelial surface significantly increased within the first twelve hours and were a major influence in the shaping of the mammary epithelium. The addition of Matrigel to the collagen fiber network impaired cell-mediated reorganization of the matrix and increased the probability of spheroidal acini rather than branching ducts. The mechanical anisotropy created by regions of highly aligned collagen fibers facilitated elongation and branching, which was significantly correlated with fiber organization. In contrast, changes in bulk stiffness were not a strong predictor of this epithelial morphology. Localized regions of collagen fiber alignment are required for ductal elongation and branching suggesting the importance of local mechanical anisotropy in mammary epithelial morphogenesis. Similar principles may govern the morphology of branching and budding in other tissues and organs.
    PLoS ONE 04/2014; 9(4):e93325. DOI:10.1371/journal.pone.0093325 · 3.23 Impact Factor
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