Molecular Cloning and Characterization of Mouse EBAG9, Homolog of a Human Cancer Associated Surface Antigen: Expression and Regulation by Estrogen

Tsuchiya, Fujiko; Ikeda, Kazuhiro; Tsutsumi, Osamu; Hiroi, Hisahiko; Momoeda, Mikio; Taketani, Yuji; Muramatsu, Masami; Inoue, Satoshi

doi:10.1006/bbrc.2001.4892

Cited by 52 publications

(57 citation statements)

References 47 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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“…Data available on the molecular mass are confusing. Calculations attribute RCAS1 a molecular mass of about 24 kDa, whereas in SDS-PAGE the gene product migrates around 32 kDa (14). According to Sonoda et al (4,5), mAb 22.1.1 immunoprecipitates generated a 78-kDa signal in SDS-PAGE gels under reducing and non-reducing conditions.…”

mentioning

confidence: 98%

“…Although RCAS1 seems to be highly conserved in phylogeny (14) and was demonstrated to have important physiological functions, little is known about the gene product itself. Data bank screens revealed that there are no homologies to any known genes or proteins.…”

mentioning

confidence: 99%

The Golgi Protein RCAS1 Controls Cell Surface Expression of Tumor-associated O-Linked Glycan Antigens

Engelsberg

Hermosilla

Karsten

et al. 2003

Journal of Biological Chemistry

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Tumor immunology has received a large impetus from the identification of tumor-associated antigens. Among them, a monoclonal antibody, 22.1.1, was instrumental in defining a novel tumor-associated antigen that was termed "receptor binding cancer antigen expressed on SiSo cells" (RCAS1). RCAS1 was proposed to induce growth arrest and apoptosis on activated immune cells, mediated by a putative death receptor. Structurally, RCAS1 was predicted to exist as a type II transmembrane protein and in a soluble form. Here, we analyzed occurrence, membrane topology, and subcellular localization of the RCAS1-encoded gene product. RCAS1 was shown to be a ubiquitously expressed type III transmembrane protein with a Golgi-predominant localization. Monoclonal antibody 22.1.1 failed to recognize RCAS1, as demonstrated by confocal microscopy. Instead, we showed that the cognate 22.1.1 epitope is identical with the tumor-associated O-linked glycan Tn (N-acetyl-D-galactosamine, GalNAc). Overexpression of RCAS1 in cell lines that are negative for 22.1.1 surface staining led to the generation of Tn and the closely related TF (Thomsen-Friedenreich, Gal␤1-3GalNAc) antigen, thus providing a functional link to the generation of the 22.1.1 epitope. We suggest that RCAS1 modulates surface expression of tumor-associated, normally cryptic O-linked glycan structures and contributes indirectly to the antigenicity of tumor cells.

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“…Recently, estrogen receptor-binding fragment-associated antigen 9 (EBAG9) has come under scrutiny (1). EBAG9 is a ubiquitously expressed protein encoded by an estrogen-responsive gene (1).…”

Section: Introductionmentioning

confidence: 99%

Intracellular estrogen receptor-binding fragment-associated antigen 9 exerts in vivo tumor-promoting effects via its coiled-coil region

Maeyama

Otsu²,

Kubo

et al. 2011

Int J Oncol

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Abstract. Estrogen receptor-binding fragment-associated antigen 9 (EBAG9) is a tumor-promoting factor of largely unknown function. To assess a causative role of EBAG9 in advanced malignancies, we generated the EG7-OVA and MethA murine tumor cell lines that stably express full-length or truncated EBAG9 protein, using retroviral-mediated gene transduction. Upon subcutaneous inoculation into immunocompetent mice, both cell lines showed marked acceleration of in vivo tumor growth when full-length EBAG9 was overexpressed. Interestingly, deletion of the coiled-coil region, thereby producing truncated EBAG9 protein, abolished the tumor-acceleration effect, establishing the importance of this domain in EBAG9-mediated tumor promotion. However, there was no alteration in in vitro cell proliferation or expression levels of MHC class I and co-stimulatory molecules believed to play a role in immune evasion of tumor cells in these tumor cell lines expressing full-length or truncated EBAG9 protein. Furthermore, both full-length and truncated EBAG9 proteins showed a predominantly cytoplasmic localization in the tumor cells. Collectively, these results suggest that EBAG9 overexpression can be causative in enhancing the malignant properties of tumor cells, and that tumor promotion likely requires EBAG9 intracellular association with as yet unidentified binding partners via the coiled-coil region.

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Molecular Cloning and Characterization of Mouse EBAG9, Homolog of a Human Cancer Associated Surface Antigen: Expression and Regulation by Estrogen

Cited by 52 publications

References 47 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

The Golgi Protein RCAS1 Controls Cell Surface Expression of Tumor-associated O-Linked Glycan Antigens

Intracellular estrogen receptor-binding fragment-associated antigen 9 exerts in vivo tumor-promoting effects via its coiled-coil region

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