Abstract Scope: Obesity is a major risk factor for the development of breast cancer whereas isoflavone (ISO) exposure is discussed to reduce this risk. Aim of this study was to investigate effects of dietary soy ISO intake on proliferation and estrogenicity of ISO in the mammary gland of obese female Wistar rats. Methods: Female Wistar rats (5 – 7 rats / group) grew up on low fat ISO-depleted diet (LF IDD) or ISO-rich diet enriched with a soy based commercial extract (LF IRD; ISO: 467 mg / kg diet). Starting postnatal day 83, ovariectomized (OVX) and intact animals received high fat diet for 12 weeks to induce obesity in the absence (HF IDD) or presence of ISO (HF IRD, ISO: 431 mg / kg diet). A special diet switch group (HF IRD switch OVX), grew up on LF IDD but switched to HF IRD after ovariectomy. This mimics the short term exposure to ISO in postmenopausal Western women who take ISO supplements. Two groups receiving LF diet either with or without ISO (LF IRD, LF IDD) lifelong served as control. From ablactation until the end of the experiment body weight and food consumption were monitored twice a week. After 12 weeks of HF diet animals were sacrificed. Body weight, visceral fat mass, and serum leptin were measured, and breast tissue was excised. Protein expression of proliferating cell nuclear antigen (PCNA) and progesterone receptor (PR) in breast tissue was analyzed by both immunohistochemistry (IHC) and Western Blot as markers for proliferation and estrogenicity of ISO, respectively. Results: Analysis of ISO plasma levels revealed 1400 nM in LF IRD group and 300 – 700 nM in HF IRD groups. HF diet increased body weight, visceral fat mass and serum leptin levels compared to LF diet. In the mammary gland HF increased expression of proliferation marker PCNA and PR as compared to LF groups. Lifelong but not short term (HF IRD switch OVX) ISO exposure reduced body weight, visceral fat mass and leptin levels in HF OVX rats. In the mammary gland lifelong ISO exposure reduced PCNA expression in both LF and HF intact animals whereas in HF OVX animals lifelong ISO exposure increased PCNA expression compared to short term ISO exposure. PR expression increased in HF IRD OVX compared to HF IDD OVX. Conclusion: The ISO plasma levels of the rats are comparable to the average ISO plasma levels as found in Asian population. Our results show that lifelong ISO intake reduces the risk to develop obesity in female rats. In the mammary gland lifelong ISO exposure decreases cell proliferation and shows estrogenicity by increasing PR expression. Effects of short term ISO exposure are less strong compared to lifelong ISO exposure. This supports the hypothesis that only lifelong but not short term ISO exposure can reduce the risk to develop breast cancer. Citation Format: Kurrat A, Diel P, Blei T, Kluxen F, Mueller D, Pichotta M, Soukup S, Kulling S, Oden C. Combined effects of soy isoflavones and a high fat diet on the mammary gland in an animal model of diet-induced obesity. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-09-03.

More and more evidence accumulates that developmental exposure to soy-derived isoflavones (sISO) considerably impacts on health outcomes later in life. The developing mammary gland (MG) for example reacts in a particularly sensitive manner to the exposure to sISO during fetal, neonatal and pubertal development. The aim of our study was to investigate the effects of a prenatally started and continuously sustained sISO exposure on the tumorigenesis of the MG in an estrogen-driven cancer model.

There is contradictory data about the consequences of isoflavone (ISO) exposure during development of female organisms. Potential impacts on tumor risk, reproduction but also altered susceptibility to develop metabolic diseases like obesity or diabetes are discussed. The aim of this study was to investigate in depth how ISO exposure during adolescence modulates the estrogen sensitivity of the uterus, vagina and visceral body fat.

There is contradictory data about the consequences of isoflavone (ISO) exposure during development of male and female organisms. Potential impacts on tumor risk, reproduction but also altered susceptibility for metabolic diseases like obesity or diabetes are discussed. An important finding in studies with females was that estrogen sensitivity evidently is affected by lifelong ISO intake. The aim of this study was to investigate whether ISOs also impact on androgen responsiveness in males. Hence we conducted a dose response experiment in male rats starting exposure in utero, maintaining it through adolescence into adulthood. Until sacrification at PND 96 rats received a diet enriched with an ISO extract in different concentrations [IDD (ISO depleted diet); IRD50 (ISO rich diet; 50 mg ISO/kg food); IRD400 (400 mg ISO/kg food)].

Abstract Background: Hundred thousands of mainly postmenopausal women are using dietary supplements enriched with soy-derived isoflavones (sISO), such as the Novasoy® extract, to relief from climacteric complaints. At the same time, hundreds of studies controversially discuss the impact of sISO on the development of breast cancer. Whether sISO positively or negatively affect the tumorigenesis of the mammary gland presumably is dependent on the time point of the sISO exposure. An exposure during gestation, lactation as well as prepubertal is believed to be preventive whereas an exposure later in life might be adverse. Objective: Aim of the study was to assess whether and how sISO influence the development of breast cancer. Therefore, August-Copenhagen-Irish (ACI) rats, a model for estrogen driven carcinogenesis, were exposed towards sISO. Dietary exposure was started preconceptional and maintained in offspring animals continuously throughout the whole individual life. Experimentals: All ACI rats were kept under controlled conditions and had ad libitum access either to a sISO-free control diet or a diet supplemented with 500ppm of the Novasoy®650 extract. Pregnant females were kept under the established dietary regimen throughout gestation and lactation period and the female offspring was investigated in the following experimental procedures. On postnatal day 60 (PND60) the animals of each dietary group randomly were implanted a 17beta-estradiol (E2) releasing (approximately 2mg release in 90 days) or a placebo pellet to induce tumorigenesis of the mammary gland. The rats were weekly palpated for mammary tumors and weighed weekly for the duration of the experiment (until PND240). Finally, we assessed physiological (e.g. organ weights, sISO exposition, mammary gland areas), (patho-)histological (HE staining), immunohistological (PCNA expression) as well as molecular end points (gene expression) of the resulting mammary gland phenotypes. Results: Control diet animals had a daily sISO exposure of ∼0.5mg/kg body weight, whereas animals of the Novasoy®650 group had a daily exposure of ∼30mg/kg body weight. Independent of the dietary background, none of the animals with an implanted placebo pellet showed tumor precursors. Ductual carcinomas in situ (DCIS) were detected in 83.3% of the animals of the control diet and in 100% of the animals of the Novasoy®650 diet, both following implantation of an E2-release pellet. Moreover, control diet animals exposed to E2 had significantly reduced mammary gland areas compared to the respective placebo group. This difference was not detectable in the Novasoy®650 dietary group. Additionally, no differences in the uterus as well as liver wet weights were noticed. On a molecular level, the expression of several genes responsible for proliferation (Ki67), estrogenicity (Tff1) and cell cycle control (Cdk4) were modified in animals lifelong exposed towards sISO. Conclusions: In ACI rats, a prenatally started and lifelong maintained sISO exposure clearly affects the estradiol induced malignant transformation of the mammary gland. This is evidenced by a higher number of DCIS as well as increased proliferation levels which were found in animals chronically exposed to sISO. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-09-03.

The effects of isoflavones (ISO) on the female breast are controversially discussed. There is evidence that ISO-rich Asian diet decreases the incidence of hormone related cancer and postmenopausal disorders. Whether chronic exposure to ISO over all critical periods of mammary gland development modulates its estrogen sensitivity was tested in a dose-dependent animal study. From in utero stages, through weaning and adolescence into adulthood female Wistar rats were exposed to different diets enriched with varying concentrations of the soy extract Novasoy650®: ISO-depleted diet (IDD), IRD50 (50 mg ISO/kg diet) and IRD400 (400 mg ISO/kg diet). Rats were ovariectomized (OVX) at day 80 and treated with 4 µg/kg BW E2 or vehicle for 3 days after 2 weeks of hormonal decline. Intact animals served as control. In a second trial adult female rats were exposed to IRD400 directly after OVX for 2 weeks and then treated with E2 as described above.

A case of prenatally diagnosed non-mosaic trisomy 20 in cells cultured from a chorionic villus sample (CVS)is presented. The term placental karyotype was also non-mosaic trisomy 20. The karyotype of the newborn was 46,XY/47,XY,+20 in foreskin cultures and in a second skin culture; blood lymphocyte culture was 46,XY. Aside from diffuse, hypopigmentary swirls along the lines of Blaschko observed on his extremities and trunk, referred to as hypomelanosis of Ito, the patient is clinically normal at 8 3/4 years of age. In addition, he is one of the oldest reported cases of mosaic trisomy 20 confirmed after birth for which the clinical outcome has been monitored. This case demonstrates that these trisomy 20 findings are compatible with normal psychomotor development and phenotype.

Partial trisomy 20p syndrome in an uncle and niece are compared to 32 previous cases.

Cytogenetic studies from 17 pediatric ependymomas and 1 ependymoblastoma are presented. Eight tumors had abnormal karyotypes. Another 107 published cases of cytogenetic analyses from pediatric and adult ependymomas or ependymoblastomas were reviewed. Of the total 125 tumors, 83 (66%) had abnormal karyotypes, of which 24 had a sole autosomal abnormality. Approximately one third had monosomy 22 (−22) or breakpoint 22q11∼13, with a higher incidence in adult (56%) versus pediatric (28%) tumors. Structural abnormalities of chromosomes 1, 6, and 17, and numerical abnormalities of 7, 9, 12, and 20, in particular, are also discussed. Although no primary cytogenetic abnormality is evident, these findings may provide direction for additional investigations regarding the classification of these tumors.

Cytogenetic studies from 17 pediatric ependymomas and 1 ependymoblastoma are presented. Eight tumors had abnormal karyotypes. Another 107 published cases of cytogenetic analyses from pediatric and adult ependymomas or ependymoblastomas were reviewed. Of the total 125 tumors, 83 (66%) had abnormal karyotypes, of which 24 had a sole autosomal abnormality. Approximately one third had monosomy 22 (-22) or breakpoint 22q11-13, with a higher incidence in adult (56%) versus pediatric (28%) tumors. Structural abnormalities of chromosomes 1, 6, and 17, and numerical abnormalities of 7, 9, 12, and 20, in particular, are also discussed. Although no primary cytogenetic abnormality is evident, these findings may provide direction for additional investigations regarding the classification of these tumors.

We report the third known case of mesenchymal hamartoma of the liver (MHL) with a balanced translocation involving a common breakpoint, 19q13.4. A common clonal chromosome abnormality appears to characterize an important subset of MHL, some of which may be low-grade neoplasms. We found no consistent karyotype abnormality in a post-treatment sample of embryonal sarcoma of the liver (ESL). Reports of coexistent MHL and ESL in two patients and detection of 19q abnormalities in two ESLs appear to support Stocker's hypothesis of a histogenetic link between these two rare liver lesions. More data are needed to clarify this relationship. It is possible that MHLs are etiologically heterogenous and may be developmental disorders, disruptions, or neoplasms.

A malignant rhabdoid tumor of the brain from a 19-month-old child was studied. Two related clones, 46,XX,-8,+der(8)t(8;22)(p11;q?12)x2,-22,del(22)(q12q?13) and 46,XX-8,+der(8)t(8;22) (p11;q?12) x2,-22,r(22) were found after chromosome analyses of primary and recurrent tumor, and multiple nude mouse passages of the tumor. Breakpoints were studied using FISH.

A 26-month-old female with trisomy 18 and repaired omphalocele died of metastatic disease after resection of hepatoblastoma (HB) at 21 months of age. Four other cases (three of them published) suggest that the association of trisomy 18 and HB may be nonrandom. Karyotype abnormalities of the tumor in our case included duplication of 2q and +20, reported previously in HB arising in patients with normal karyotype. Antecedent growth disturbance of liver, either intrinsic (abnormal lobation) or related to contiguous extrinsic anomalies such as omphalocele or local diaphragmatic hypoplasia and possibly augmented by unusual sensitivity to noxious environmental agents, may predispose to hepatoblastoma in trisomy 18. Longevity in trisomy 18 predisposes to both hepatoblastoma and Wilms tumor, possibly by a shared pathway.

A partial duplication (1)(p21p31), resulting from a maternal direct insertion (13,1) (q22p21p31), was found in a 30-year-old woman with mental retardation, cleft palate, and multiple minor anomalies. Two other affected and deceased relatives were presumed to have the same chromosome imbalance. Duplication 1p cases are reviewed.

A 15-month-old boy with mild developmental delay and several minor anomalies was found to be mosaic 46,XY/47,XY ,+mar(1). The marker r(1) was a small de novo ring identified by FISH with a painting type DNA probe.

A child without Down syndrome but with developmental delay, short stature, and autistic behavior was found to be mosaic 46,XX/47,XX,+mar(21) de novo. The marker was a small ring or dot-like chromosome. Microdissection of the marker was performed. The dissected fragments were biotinylated with sequence-independent PCR as a probe pool for fluorescence in situ hybridization (FISH). FISH results suggested an acrocentric origin of the marker. Subsequent FISH with alpha-satellite DNA probes for acrocentric chromosomes, and chromosome-specific 21 and 22 painting probes confirmed its origin from chromosome 21.