EBAG9/RCAS1 in human breast carcinoma: a possible factor in endocrine–immune interactions

Suzuki, Takashi; Inoue, Satoshi; Kawabata, Wakako; Akahira, Jun Ichi; Moriya, Takuya; Tsuchiya, Fujiko; Ogawa, Sumito; Muramatsu, Masami; Sasano, Hironobu

doi:10.1054/bjoc.2001.2176

Cited by 51 publications

(57 citation statements)

References 40 publications

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“…EBAG9 has been shown to be expressed at a very low level in MDA-MB-231 cells without the addition of estrogen, and robustly expressed after estrogen treatment in ER␣ positive MCF-7 cells (15). When ER␣-positive breast cancer cells are treated with tamoxifen, the mRNA expression of both CATD and EBAG9 is repressed (35,36). MDA-MB-231 cells were grown in hormone free medium and stimulated with rWnt-5a or Foxy-5.…”

Section: Resultsmentioning

confidence: 99%

RETRACTED: Wnt-5a signaling restores tamoxifen sensitivity in estrogen receptor-negative breast cancer cells

Ford

Ekström

Andersson

2009

Proc. Natl. Acad. Sci. U.S.A.

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One third of all breast cancers are estrogen receptor alpha (ERα) negative, carry a poor overall prognosis, and do not respond well to currently available endocrine therapies. New treatment strategies are therefore required. Loss of Wnt-5a has previously been correlated with loss of ERα in clinical breast cancer samples, and we sought to investigate this association further. Three breast cancer cell lines (MDA-MB-231, MDA-MB-468, and 4T1) lacking expression of ERα and Wnt-5a, and one breast cancer cell line (T47D) expressing both proteins were used in this study. Wnt-5a signaling was generated in ERα-negative cell lines via stimulation with either recombinant Wnt-5a protein or a Wnt-5a-derived hexapeptide (Foxy-5) possessing Wnt-5a signaling properties. ERα expression was restored at both mRNA and protein level, after treatment with recombinant Wnt-5a or Foxy-5. This restoration of expression occurred in parallel with a reduction in methylation of the ERα promoter. Up-regulated ERα could be activated, initiate transcription of progesterone receptor and pS2, and activate an estrogen response element reporter construct. Significantly, breast cancer cells re-expressing ERα responded to treatment with the selective estrogen receptor modulator tamoxifen, as measured by induction of apoptosis and cell growth inhibition. Finally, Foxy-5 also increased ERα expression in an in vivo model of ERα-negative breast cancer. This represents the first evidence that Wnt-5a signaling acts to re-establish ERα expression in ERα-negative breast cancer cells. Our data suggest that combinatorial therapy with Foxy-5 and tamoxifen should be considered as a future treatment possibility for ERα-negative breast cancer patients.

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Section: Resultsmentioning

confidence: 99%

RETRACTED: Wnt-5a signaling restores tamoxifen sensitivity in estrogen receptor-negative breast cancer cells

Ford

Ekström

Andersson

2009

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition, Sonoda et al (1998) reported that RCAS1 was not detected in the normal uterine cervix or ovarian tissue, but strongly expressed in uterine endometrial adenocarcinomas, ovarian adenocarcinomas (Sonoda et al, 1996;Sonoda et al, 2000) and cervical squamous cell carcinomas. Recently, Suzuki et al (2001) reported that EBAG9 immunoreactivity was detected in 82 of 91 in breast carcinoma (90.1%), although it was not associated with clinicopathological parameters. Others reported that EBAG9 gene was consistently expressed in breast cancer cell line, and might play a specific role in early stages of breast carcinogenesis (Tsuneizumi et al, 2001).…”

Section: Discussionmentioning

confidence: 96%

Expression of EBAG9/RCAS1 is associated with advanced disease in human epithelial ovarian cancer

Aoki

Suzuki

et al. 2004

Br J Cancer

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Oestrogen receptor-binding fragment associated gene 9, EBAG9, is an oestrogen-responsive gene that was identified in MCF-7 human breast carcinoma cell line. It is identical to RCAS 1, a cancer cell surface antigen possibly involved in immune escape. In the present study, we examined the expression of EBAG9/RCAS1 in human epithelial ovarian cancer using immunohistochemistry, immunoblotting and reverse transcription -polymerase chain reaction (RT -PCR). A total of 90 epithelial ovarian cancer cases were examined immunohistochemically by means of the antibodies for EBAG9 and ERa. The correlation between EBAG9 immunoreactivity and clinicopathological parameters was examined. mRNA expression of EBAG9 and ERa were evaluated by RT -PCR in 22 cases. The expression for EBAG9 and ERa was examined by immunoblotting in 12 ovarian cancer cell lines. EBAG9 immunoreactivity was detected in the surface and cytoplasm of carcinoma cells in 46 out of 90 cases (51.1%). EBAG9 expression was significantly higher in serous histology (P ¼ 0.0402) and advanced disease (P ¼ 0.0206). No significant relationship was detected between EBAG9 immunoreactivity and overall survival (P ¼ 0.689). There was a highly significant correlation between EBAG9 and ER immunoreactivity (Po0.0001). The EBAG9 mRNA was detected in 20 out of 22 cases. In all of the cases that were positive for ERa mRNA, they were also positive for EBAG9 mRNA. Immunoreactive band corresponding to EBAG9 was detected in 11 out of 12 of ovarian cancer cell lines, and was consistent with ERa expression. In conclusion, the wide distribution of EBAG9 and its relation to advanced disease suggest that this protein may play important roles in epithelial ovarian cancer.

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“…Tumor size was measured weekly with a micrometer in two dimensions, and tumor volume was estimated according to the formula: (smallest diameter) 2 Â (longest diameter). When the volumes of tumors reached 300 mm 3 , siRNA duplexes (10 Ag) were injected directly into tumors twice every week, along with 4 AL of GeneSilencer (Gene Therapy System, San Diego, CA) dissolved in 0.1 mL of Opti-MEM (Life Technologies, Gaithersburg, MD). Mice were sacrificed 4 weeks after treatment.…”

Section: Methodsmentioning

confidence: 99%

Estrogen Receptor–Binding Fragment–Associated Antigen 9 Is a Tumor-Promoting and Prognostic Factor for Renal Cell Carcinoma

Ogushi¹,

Takahashi²,

Takeuchi³

et al. 2005

Cancer Research

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The estrogen receptor-binding fragment-associated antigen 9 (EBAG9) has been identified as a primary estrogenresponsive gene in human breast cancer MCF7 cells. A high expression of EBAG9 has been observed in invasive breast cancer and advanced prostate cancer, suggesting a tumorpromoting role of the protein in malignancies. Here we show that intratumoral (i.t.) administration of small interfering RNA against EBAG9 exerted overt regression of tumors following s.c. implantation of murine renal cell carcinoma (RCC) Renca cells. Overexpression of EBAG9 did not promote the proliferation of culture Renca cells; however, the inoculated Renca cells harboring EBAG9 (Renca-EBAG9) in BALB/c mice grew faster and developed larger tumors compared with Renca cells expressing vector alone (Rencavector). After renal subcapsular implantation, Renca-EBAG9 tumors significantly enlarged compared with Renca-vector tumors in BALB/c mice, whereas both Renca-EBAG9 and Renca-vector tumors were developed with similar volumes in BALB/c nude mice. No apparent difference was observed in specific cytotoxic T-cell responses against Renca-EBAG9 and Renca-vector cells; nonetheless, the number of infiltrating CD8 + T lymphocytes was decreased in Renca-EBAG9 subcapsular tumors. Furthermore, immunohistochemical study of EBAG9 in 78 human RCC specimens showed that intense and diffuse cytoplasmic immunostaining was observed in 87% of the cases and positive EBAG9 immunoreactivity was closely correlated with poor prognosis of the patients. Multivariate analysis revealed that high EBAG9 expression was an independent prognostic predictor for disease-specific survival (P = 0.0485). Our results suggest that EBAG9 is a crucial regulator of tumor progression and a potential prognostic marker for RCC. (Cancer Res 2005; 65(9): 3700-6)

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EBAG9/RCAS1 in human breast carcinoma: a possible factor in endocrine–immune interactions

Cited by 51 publications

References 40 publications

RETRACTED: Wnt-5a signaling restores tamoxifen sensitivity in estrogen receptor-negative breast cancer cells

RETRACTED: Wnt-5a signaling restores tamoxifen sensitivity in estrogen receptor-negative breast cancer cells

Expression of EBAG9/RCAS1 is associated with advanced disease in human epithelial ovarian cancer

Estrogen Receptor–Binding Fragment–Associated Antigen 9 Is a Tumor-Promoting and Prognostic Factor for Renal Cell Carcinoma

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