The BCL9-2 proto-oncogene governs estrogen receptor alpha expression in breast tumorigenesis

The majority of human breast cancers express estrogen receptor {Alpha} (ER), which is important for therapy with anti-estrogens. Here we describe the role of BCL9-2, a proto-oncogene previously characterized as co-activator of Wnt/{beta}-catenin signaling, for mammary tumorigenesis in mice and human. ER positive human breast cancers showed overexpression of BCL9-2 and tamoxifen treated patients with high BCL9-2 demonstrated a better survival. BCL9-2 was upregulated during puberty and pregnancy in normal mammary epithelia, but downregulated in the involuted gland. BCL9-2 overexpression in vivo delayed the mammary involution and induced alveolar hyperplasia. Moreover, aged BCL9-2 transgenic mice developed ductal-like mammary tumors with high nuclear ER expression. We found, that primary cell cultures of BCL9-2 breast tumors responded to tamoxifen treatment. Moreover, BCL9-2 regulated the expression of ER and the proliferation of human breast cancer cells independently of {beta}-catenin. Finally, we describe a novel mechanism, how BCL9-2 regulates ER transcription by interaction with Sp1 through the proximal ESR1 gene promoter. In summary, BCL9-2 induces ER positive breast cancers in vivo, regulates ER expression by a novel {beta}-catenin independent mechanism in breast cancer cells, and might predict the therapy response to tamoxifen treatment

LINE-1 retrotransposon methylation in chorionic villi of first trimester miscarriages with aneuploidy

Purpose High frequency of aneuploidy in meiosis and cleavage stage coincides with waves of epigenetic genome reprogramming that may indicate a possible association between epigenetic mechanisms and aneuploidy occurrence. This study aimed to assess the methylation level of the long interspersed repeat element 1 (LINE-1) retrotransposon in chorionic villi of first trimester miscarriages with a normal karyotype and aneuploidy. Methods The methylation level was assessed at 19 LINE-1 promoter CpG sites in chorionic villi of 141 miscarriages with trisomy of chromosomes 2, 6, 8-10, 13-15, 16, 18, 20-22, and monosomy X using massive parallel sequencing. Results The LINE-1 methylation level was elevated statistically significant in chorionic villi of miscarriages with both trisomy (45.2 +/- 4.3%) and monosomy X (46.9 +/- 4.2%) compared with that in induced abortions (40.0 +/- 2.4%) (p < 0.00001). The LINE-1 methylation levels were specific for miscarriages with different aneuploidies and significantly increased in miscarriages with trisomies 8, 14, and 18 and monosomy X (p < 0.05). The LINE-1 methylation level increased with gestational age both for group of miscarriages regardless of karyotype (R = 0.21, p = 0.012) and specifically for miscarriages with trisomy 16 (R = 0.48, p = 0.007). LINE-1 methylation decreased with maternal age in miscarriages with a normal karyotype (R = - 0.31, p = 0.029) and with trisomy 21 (R = - 0.64, p = 0.024) and increased with paternal age for miscarriages with trisomy 16 (R = 0.38, p = 0.048) and monosomy X (R = 0.73, p = 0.003). Conclusion Our results indicate that the pathogenic effects of aneuploidy in human embryogenesis can be supplemented with significant epigenetic changes in the repetitive sequences

Математичне моделювання напруженого стану в'язкопружної напівплощини з включеннями

The application of the method of boundary integral equations is considered for studying the stress state of flat viscoelastic bodies with inclusions. The method is based on the use of complex potentials and the apparatus of generalized functions. An analytical solution of the problem is obtained for a half-plane with inclusions of arbitrary shape. For a numerical study of the change in the stress state depending on the time and geometry of the inclusions, a discrete analogue of the system of boundary-time integral equations has been developed. Pages of the article in the issue: 42 - 45 Language of the article: EnglishРозглянуто застосування методу граничних інтегральних рівнянь при дослідженні напруженого стану плоских в'язкопружних тіл із включеннями. Метод базується на використанні комплексних потенціалів та апарату узагальнених функцій. Отримано аналітичний розв'язок задачі для напівплощини із довільними за формою включеннями. Для чисельного дослідження зміни напруженого стану залежно від часу та геометрії включень було розроблено дискретний аналог системи гранично-часових інтегральних рівнянь

Апроксимація щільностей потенціалів для плоских в'язкопружних тіл із включеннями, що обмежені кусково-гладкими контурами

An approach for approximating unknown densities of potentials in the study of the stressed state of a flat viscoelastic piecewise homogeneous body with inclusions, bounded by piecewise smooth contours, is proposed. The method is based on the construction of a system of boundary-time integral equations to determine the unknown densities of potentials along the contours of the inclusions. The approximation of the unknown densities of potentials was performed taking into account the singularity of the stressed state of a flat viscoelastic body near the angular point of the dividing line of the regions. Pages of the article in the issue: 39 - 42 Language of the article: EnglishЗапропоновано підхід апроксимації невідомих щільностей потенціалів при дослідженні напруженого стану плоского в'язкопружного кусково-однорідного тіла з включеннями, що обмежені кусково-гладкими контурами. Метод базується на побудові системи гранично-часових інтегральних рівнянь для визначення невідомих щільностей потенціалів по контурах включень. Апроксимація невідомих щільностей потенціалів здійснювалася з урахуванням особливості напруженого стану плоского в'язкопружного тіла поблизу кутової точки лінії розділу областей. Pages of the article in the issue: 39 - 42 Language of the article: Englis

BCL9-2 promotes early stages of intestinal tumor progression

BACKGROUND & AIMS: The roles of the 2 BCL9 and 2 Pygopus genes in Wnt to beta-catenin signaling are not clear in vertebrates. We examined their expression and function in normal and tumor intestinal epithelia in mice and humans. METHODS: Specific antibodies were generated to characterize the BCL9 and Pygopus proteins in normal intestine and in colon tumors. Targets of BCL9 and Pygopus in colon cancer cells were analyzed using small interfering (si) RNA analysis. Trangenic mice were created that overexpressed BCL9-2 in intestine; these were crossed with APC(Min/+) mice to create BCL9-2;APC(Min/+) mice. RESULTS: BCL9 and Pygopus2 were expressed in all normal intestinal and colon cancer cells. BCL9-2 was detectable only in the villi-not in the crypts of normal intestine. BCL9-2 was upregulated in adenomas and in almost all colon tumors, with a concomitant increase of Pygopus2, whereas levels of BCL9 were similar between normal and cancer cells. Transgenic overexpression of BCL9-2 in the intestine of BCL9-2; APC(Min/+) mice increased formation of adenomas that progressed to invasive tumors, resulting in reduced survival time. Using siRNA analysis, we found that BCL9s and Pygopus are not targets of Wnt in colon cancer cells, but Wnt signaling correlated with levels of BCL9-2. BCL9-2 regulated expression of beta-catenin-dependent and -independent target genes that have been associated with early stages of intestinal tumorigenesis. DISCUSSION: BCL9-2 promotes early phases of intestinal tumor progression in humans and in transgenic mice. BCL9-2 increases the expression of a subset of canonical Wnt target genes, but also regulates genes that are required for early stages of tumor progression