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

Zatula N, Wiese M, Bunzendahl J, Birchmeier W, Perske C, Bleckmann A, Brembeck FH - Oncotarget (2014)

Bottom Line: BCL9-2 overexpression in vivo delayed the mammary involution and induced alveolar hyperplasia.We found, that primary cell cultures of BCL9-2 breast tumors responded to tamoxifen treatment.Finally, we describe a novel mechanism, how BCL9-2 regulates ER transcription by interaction with Sp1 through the proximal ESR1 gene promoter.

View Article: PubMed Central - PubMed

Affiliation: Tumor Biology and Signal Transduction, Georg-August-University Göttingen, Germany. Dept. of Hematology and Medical Oncology, Georg-August-University Göttingen, Germany.

ABSTRACT
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/ß-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 ß-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 ß-catenin independent mechanism in breast cancer cells, and might predict the therapy response to tamoxifen treatment.

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In vivo overexpression of BCL9-2 delays the postlactational and age-related involution and induces preneoplastic changes of the mammary gland in mice(A) Carmine stains and immunohistochemistry with the indicated antibodies of representative mammary glands of four month old non-transgenic and BCL9-2 females after pregnancy. Shown are mammary tissues on day 10 of involution. (B) Box-Plot analyses of the scoring (upper panel) and representative carmine stains (lower panel) for the indicated preneoplastic changes in the aged mammary gland. Age-matched non-transgenic (white bars) and BCL9-2 virgin females from four different founder lines (grey bars) were analyzed at 22.0 ± 2.0 month of age. Each group represents at least six animals. The asterisk marks significant differences with P<.05. (C) Representative stains of mammary glands from age-matched, 20 month old non-transgenic and BCL9-2 virgin females. Scale bars in the pictures represent 2 mm for carmine stains, 200 μm for H&E, and 50 μm for IHC. Inserts show the staining at higher magnification.
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Figure 3: In vivo overexpression of BCL9-2 delays the postlactational and age-related involution and induces preneoplastic changes of the mammary gland in mice(A) Carmine stains and immunohistochemistry with the indicated antibodies of representative mammary glands of four month old non-transgenic and BCL9-2 females after pregnancy. Shown are mammary tissues on day 10 of involution. (B) Box-Plot analyses of the scoring (upper panel) and representative carmine stains (lower panel) for the indicated preneoplastic changes in the aged mammary gland. Age-matched non-transgenic (white bars) and BCL9-2 virgin females from four different founder lines (grey bars) were analyzed at 22.0 ± 2.0 month of age. Each group represents at least six animals. The asterisk marks significant differences with P<.05. (C) Representative stains of mammary glands from age-matched, 20 month old non-transgenic and BCL9-2 virgin females. Scale bars in the pictures represent 2 mm for carmine stains, 200 μm for H&E, and 50 μm for IHC. Inserts show the staining at higher magnification.

Mentions: To study a potential role of BCL9-2 as proto-oncogene in the mammary gland, we analyzed the in vivo overexpression of BCL9-2 in transgenic mice. Our K19-BCL9-2 mouse model (on a pure C57BL/6 background) induces BCL9-2 overexpression by the Keratin 19 (K19) gene promoter, which targets in the breast fully developed luminal cells and putative luminal progenitors [15; 29; 30]. We asked if BCL9-2 overexpression may affect the normal postnatal mammary development or can induce atypical preneoplastic lesions in vivo. For this, we analyzed BCL9-2 mice and age-matched non-transgenic controls by immunohistochemistry on tissue sections and carmine whole mount stains (Fig. 3).


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

Zatula N, Wiese M, Bunzendahl J, Birchmeier W, Perske C, Bleckmann A, Brembeck FH - Oncotarget (2014)

In vivo overexpression of BCL9-2 delays the postlactational and age-related involution and induces preneoplastic changes of the mammary gland in mice(A) Carmine stains and immunohistochemistry with the indicated antibodies of representative mammary glands of four month old non-transgenic and BCL9-2 females after pregnancy. Shown are mammary tissues on day 10 of involution. (B) Box-Plot analyses of the scoring (upper panel) and representative carmine stains (lower panel) for the indicated preneoplastic changes in the aged mammary gland. Age-matched non-transgenic (white bars) and BCL9-2 virgin females from four different founder lines (grey bars) were analyzed at 22.0 ± 2.0 month of age. Each group represents at least six animals. The asterisk marks significant differences with P<.05. (C) Representative stains of mammary glands from age-matched, 20 month old non-transgenic and BCL9-2 virgin females. Scale bars in the pictures represent 2 mm for carmine stains, 200 μm for H&E, and 50 μm for IHC. Inserts show the staining at higher magnification.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4196162&req=5

Figure 3: In vivo overexpression of BCL9-2 delays the postlactational and age-related involution and induces preneoplastic changes of the mammary gland in mice(A) Carmine stains and immunohistochemistry with the indicated antibodies of representative mammary glands of four month old non-transgenic and BCL9-2 females after pregnancy. Shown are mammary tissues on day 10 of involution. (B) Box-Plot analyses of the scoring (upper panel) and representative carmine stains (lower panel) for the indicated preneoplastic changes in the aged mammary gland. Age-matched non-transgenic (white bars) and BCL9-2 virgin females from four different founder lines (grey bars) were analyzed at 22.0 ± 2.0 month of age. Each group represents at least six animals. The asterisk marks significant differences with P<.05. (C) Representative stains of mammary glands from age-matched, 20 month old non-transgenic and BCL9-2 virgin females. Scale bars in the pictures represent 2 mm for carmine stains, 200 μm for H&E, and 50 μm for IHC. Inserts show the staining at higher magnification.
Mentions: To study a potential role of BCL9-2 as proto-oncogene in the mammary gland, we analyzed the in vivo overexpression of BCL9-2 in transgenic mice. Our K19-BCL9-2 mouse model (on a pure C57BL/6 background) induces BCL9-2 overexpression by the Keratin 19 (K19) gene promoter, which targets in the breast fully developed luminal cells and putative luminal progenitors [15; 29; 30]. We asked if BCL9-2 overexpression may affect the normal postnatal mammary development or can induce atypical preneoplastic lesions in vivo. For this, we analyzed BCL9-2 mice and age-matched non-transgenic controls by immunohistochemistry on tissue sections and carmine whole mount stains (Fig. 3).

Bottom Line: BCL9-2 overexpression in vivo delayed the mammary involution and induced alveolar hyperplasia.We found, that primary cell cultures of BCL9-2 breast tumors responded to tamoxifen treatment.Finally, we describe a novel mechanism, how BCL9-2 regulates ER transcription by interaction with Sp1 through the proximal ESR1 gene promoter.

View Article: PubMed Central - PubMed

Affiliation: Tumor Biology and Signal Transduction, Georg-August-University Göttingen, Germany. Dept. of Hematology and Medical Oncology, Georg-August-University Göttingen, Germany.

ABSTRACT
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/ß-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 ß-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 ß-catenin independent mechanism in breast cancer cells, and might predict the therapy response to tamoxifen treatment.

Show MeSH
Related in: MedlinePlus