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Review
. 2008 Feb;102(2):125-33.
doi: 10.1111/j.1742-7843.2007.00165.x.

Does Breast Cancer Start in the Womb?

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Free PMC article
Review

Does Breast Cancer Start in the Womb?

Ana M Soto et al. Basic Clin Pharmacol Toxicol. .
Free PMC article

Abstract

Perturbations in the foetal environment predispose individuals to diseases that become apparent in adulthood. These findings prompted researchers to hypothesize that foetal exposure to environmental oestrogens may play a role in the increased incidence of breast cancer observed in European and US populations over the last 50 years. There is widespread human exposure to bisphenol A, an oestrogenic compound that leaches from dental materials and consumer products. In CD-1 mice, perinatal exposure to environmentally relevant bisphenol A levels induced alterations of the mammary gland architecture. Bisphenol A increased the number of terminal end buds at puberty and terminal ends at 6 months of age and increased ductal lateral branching at 4 months of age. Exposed mice also showed an enhanced sensitivity to oestradiol when ovariectomized prior to puberty. All these parameters are associated in human beings with an increased risk for developing breast cancer. To assess whether bisphenol A induces mammary gland neoplasia, we chose a rat model because it more closely mimics the human disease than mouse models. Examination of the mammary glands of Wistar/Furth rats during early adulthood revealed that gestational exposure to bisphenol A induced the development of pre-neoplastic lesions and carcinoma in situ in the absence of any additional treatment aimed at increasing tumour development. Emerging epidemiological data reveal an increased incidence of breast cancer in women exposed to diethylstilboestrol during gestation. Hence, both animal experiments and epidemiological data strengthen the hypothesis that foetal exposure to xenooestrogens may be an underlying cause of the increased incidence of breast cancer observed over the last 50 years.

Figures

Fig. 1
Fig. 1
Morphometric parameters in the mammary gland of ovariectomized pubertal mice demonstrate non-monotonic dose–response curves in response to oestradiol. The dashed line denotes the number of terminal end buds (TEB) and the solid line denotes TEB area. * or indicates the dose where the maximal response was observed, which is statistically different from both its ovariectomized control and the highest administered dose (marked with the ** or ††).
Fig. 2
Fig. 2
Chemical structures of bisphenol A (BPA), diethylstilbestrol (DES) and oestradiol. The structures of BPA and DES are more similar to one another than they are to the endogenous oestradiol, indicating that chemicals with variable structures are capable of binding to the oestrogen receptor.
Fig. 3
Fig. 3
Appearance of the mammary gland at embryonic day 18. (A) Branching points (arrows) are apparent in carmine stained whole mounts. (B) Haematoxylin and eosin-stained paraffin section, demonstrating lumen formation (arrowhead), which is evident in approximately 40% of untreated glands at this age. (C) Lipid droplets are observed in clusters of primitive fat pad (fp) within a short distance of the epithelium (see inset). Ep, epithelium.
Fig. 4
Fig. 4
In utero exposure to bisphenol A (BPA) alters tissue organization in the mammary gland at several distinct developmental periods. (A) Ductal area and ductal extension are significantly increased at E18 in BPA-exposed foetuses. (B) Perinatal BPA exposure alters the number of terminal end buds (TEB) and the TEB area relative to total ductal area in the pubertal mammary gland. (C) Perinatally exposed females demonstrate increases in the relative area of ducts, terminal ends and alveolar buds in adulthood (6 months of age). Area of ducts and alvelolar buds: left axis; terminal ends: right axis. * denotes significant differences between animals exposed to 250 ng BPA/kg/day (250 BPA) and the vehicle control (0 BPA).
Fig. 5
Fig. 5
Perinatal bisphenol A (BPA) exposure alters the sensitivity of the mammary gland to oestradiol at puberty. Animals exposed perinatally to vehicle (0 BPA) or 250 ng BPA/kg/day (250 BPA) were ovariectomized and challenged with 0 (−E2) or 0.5 μg oestradiol/kg/day (+E2) at 25 days of age (pre-puberty). BPA-exposed animals had a heightened response in number of terminal end buds (TEB) compared to control animals. * denotes significant differences from −E2 groups. The symbol ‘’ indicates significant differences from animals exposed perinatally to vehicle and to E2 at 25 days of age.
Fig. 6
Fig. 6
Neoplastic lesions. The percentage of ductal hyperplasias is significantly increased in bisphenol A (BPA)-exposed animals at postnatal day 50 (A) and 95 (D); *P < 0.05; **P < 0.005. Some of the ductal lesions were identified as carcinomas in situ (CIS) and had a cribriform pattern. This can be observed at postnatal day 50 (B and C) and 95 (E and F). The CIS showed not only multiple lumina but also hyperchromatic nuclear staining with visible nucleoli (inset in E and F). Scale bar: 50 μm (figure reproduced with permission, Reproductive Toxicology; 23:383–390, 2007).

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