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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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BCL9-2 is highly expressed in human ER+ breast cancers and might predict the response to tamoxifen treatment(A) Representative immunostains for BCL9-2 on human breast tissue microarrays. Shown are examples for normal human breast tissues and breast cancers (CA) with (“+”) or without (“-“) positivity for ER or Her2 based on the immunoreactive scores. (B) Immunofluorescence stains and merged pictures for BCL9-2, ER and SMA. Shown are serial sections from a human breast tissue microarray with an example of normal human breast tissue and an ER+ breast cancer. The scale bar represents 50 μM. (C, D) Box plot analysis of the BCL9-2 immunoreactive score in normal human breast tissues (N; n=30) and breast cancer samples (CA; n=194). BCL9-2 scores were further plotted for the pathological grade (B; G1-G3: n= 16; 116; 38; respectively) and for ER/PR or Her2 positivity (C; triple negative: n=48; Her2+: n=64; ER/PR+: n=26; ER/PR and Her2+: n=53). P-values are indicated in the graphs with n.s. = not significant; *P<.05; ** P<.005; *** P<.001 (Mann-Whitney test). (E) Kaplan-Meier analysis for the relapse free survival of tamoxifen treated patients with ER+ breast cancers. BCL9-2 expression data were derived from microarray analyses [GSE 6532, 28]. High (n=129) or low (n= 134) BCL9-2 was relative to the median expression of all samples. Significance was calculated using the Cox Proportional Hazard Model.
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Figure 1: BCL9-2 is highly expressed in human ER+ breast cancers and might predict the response to tamoxifen treatment(A) Representative immunostains for BCL9-2 on human breast tissue microarrays. Shown are examples for normal human breast tissues and breast cancers (CA) with (“+”) or without (“-“) positivity for ER or Her2 based on the immunoreactive scores. (B) Immunofluorescence stains and merged pictures for BCL9-2, ER and SMA. Shown are serial sections from a human breast tissue microarray with an example of normal human breast tissue and an ER+ breast cancer. The scale bar represents 50 μM. (C, D) Box plot analysis of the BCL9-2 immunoreactive score in normal human breast tissues (N; n=30) and breast cancer samples (CA; n=194). BCL9-2 scores were further plotted for the pathological grade (B; G1-G3: n= 16; 116; 38; respectively) and for ER/PR or Her2 positivity (C; triple negative: n=48; Her2+: n=64; ER/PR+: n=26; ER/PR and Her2+: n=53). P-values are indicated in the graphs with n.s. = not significant; *P<.05; ** P<.005; *** P<.001 (Mann-Whitney test). (E) Kaplan-Meier analysis for the relapse free survival of tamoxifen treated patients with ER+ breast cancers. BCL9-2 expression data were derived from microarray analyses [GSE 6532, 28]. High (n=129) or low (n= 134) BCL9-2 was relative to the median expression of all samples. Significance was calculated using the Cox Proportional Hazard Model.

Mentions: Since BCL9 proteins are implicated in cancer development and progression, we analyzed their expression and role in normal and malignant breast tissues. First, we characterized BCL9 proteins in human tissue samples and during different stages of postnatal mammary gland development in the mouse (Fig. 1 and 2, Suppl. Fig. 1). For immunostains we used our specific antibodies against BCL9 and BCL9-2 [15] and re-confirmed their specificity on mammary tissues by peptide competition (Suppl. Fig. 1D-F).


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)

BCL9-2 is highly expressed in human ER+ breast cancers and might predict the response to tamoxifen treatment(A) Representative immunostains for BCL9-2 on human breast tissue microarrays. Shown are examples for normal human breast tissues and breast cancers (CA) with (“+”) or without (“-“) positivity for ER or Her2 based on the immunoreactive scores. (B) Immunofluorescence stains and merged pictures for BCL9-2, ER and SMA. Shown are serial sections from a human breast tissue microarray with an example of normal human breast tissue and an ER+ breast cancer. The scale bar represents 50 μM. (C, D) Box plot analysis of the BCL9-2 immunoreactive score in normal human breast tissues (N; n=30) and breast cancer samples (CA; n=194). BCL9-2 scores were further plotted for the pathological grade (B; G1-G3: n= 16; 116; 38; respectively) and for ER/PR or Her2 positivity (C; triple negative: n=48; Her2+: n=64; ER/PR+: n=26; ER/PR and Her2+: n=53). P-values are indicated in the graphs with n.s. = not significant; *P<.05; ** P<.005; *** P<.001 (Mann-Whitney test). (E) Kaplan-Meier analysis for the relapse free survival of tamoxifen treated patients with ER+ breast cancers. BCL9-2 expression data were derived from microarray analyses [GSE 6532, 28]. High (n=129) or low (n= 134) BCL9-2 was relative to the median expression of all samples. Significance was calculated using the Cox Proportional Hazard Model.
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Figure 1: BCL9-2 is highly expressed in human ER+ breast cancers and might predict the response to tamoxifen treatment(A) Representative immunostains for BCL9-2 on human breast tissue microarrays. Shown are examples for normal human breast tissues and breast cancers (CA) with (“+”) or without (“-“) positivity for ER or Her2 based on the immunoreactive scores. (B) Immunofluorescence stains and merged pictures for BCL9-2, ER and SMA. Shown are serial sections from a human breast tissue microarray with an example of normal human breast tissue and an ER+ breast cancer. The scale bar represents 50 μM. (C, D) Box plot analysis of the BCL9-2 immunoreactive score in normal human breast tissues (N; n=30) and breast cancer samples (CA; n=194). BCL9-2 scores were further plotted for the pathological grade (B; G1-G3: n= 16; 116; 38; respectively) and for ER/PR or Her2 positivity (C; triple negative: n=48; Her2+: n=64; ER/PR+: n=26; ER/PR and Her2+: n=53). P-values are indicated in the graphs with n.s. = not significant; *P<.05; ** P<.005; *** P<.001 (Mann-Whitney test). (E) Kaplan-Meier analysis for the relapse free survival of tamoxifen treated patients with ER+ breast cancers. BCL9-2 expression data were derived from microarray analyses [GSE 6532, 28]. High (n=129) or low (n= 134) BCL9-2 was relative to the median expression of all samples. Significance was calculated using the Cox Proportional Hazard Model.
Mentions: Since BCL9 proteins are implicated in cancer development and progression, we analyzed their expression and role in normal and malignant breast tissues. First, we characterized BCL9 proteins in human tissue samples and during different stages of postnatal mammary gland development in the mouse (Fig. 1 and 2, Suppl. Fig. 1). For immunostains we used our specific antibodies against BCL9 and BCL9-2 [15] and re-confirmed their specificity on mammary tissues by peptide competition (Suppl. Fig. 1D-F).

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