Skip to main content
Top
Published in: Breast Cancer Research 5/2009

Open Access 01-10-2009 | Research article

Steroid Receptor RNA Activator Protein (SRAP): a potential new prognostic marker for estrogen receptor-positive/node-negative/younger breast cancer patients

Authors: Yi Yan, George P Skliris, Carla Penner, Shilpa Chooniedass-Kothari, Charlton Cooper, Zoann Nugent, Anne Blanchard, Peter H Watson, Yvonne Myal, Leigh C Murphy, Etienne Leygue

Published in: Breast Cancer Research | Issue 5/2009

Login to get access

Abstract

Introduction

The steroid receptor RNA activator is a functional RNA suspected to participate in the mechanisms underlying breast tumor progression. This RNA is also able to encode for a protein, Steroid Receptor RNA Activator Protein (SRAP), whose exact function remains to be determined. Our aim was to assess, in a large breast cancer cohort, whether levels of this protein could be associated with outcome or established clinical parameters.

Methods

Following antibody validation, SRAP expression was assessed by tissue-microarray (TMA) analysis of 372 breast tumors. Clinical follow-up and parameters such as steroid receptor and node status were available for all the corresponding cases. Immunohistochemical scores were independently determined by three investigators and averaged. Statistical analyses were performed using standard univariate and multivariate tests.

Results

SRAP levels were significantly (Mann-Whitney rank sum test, P < 0.05) higher in estrogen receptor-alpha positive (ER+, n = 271), in progesterone receptor positive (PR+, n = 257) and in older patients (age > 64 years, n = 182). When considering ER+ tumors, PR+ tumors, or younger patients (≤ 64 years), cases with high SRAP expression had a significantly (Mantel-Cox test, P < 0.05) worse breast cancer specific survival (BCSS) than those with low SRAP levels. SRAP also appeared as a very powerful indicator of poor prognostic for BCSS in the subset of ER+, node negative and young breast cancer patients (Cox regression analysis, n = 60, BCSS Hazard Ratio = 8.61, P < 0.006).

Conclusions

Our data suggest that SRAP levels might provide additional information on potential risk of recurrence and negative outcome in a specific set of patients with otherwise good prognosis when considering only estrogen receptor and nodal status.
Appendix
Available only for authorised users
Literature
1.
go back to reference Porter P: "Westernizing" women's risks? Breast cancer in lower-income countries. N Engl J Med. 2008, 358: 213-216. 10.1056/NEJMp0708307.CrossRefPubMed Porter P: "Westernizing" women's risks? Breast cancer in lower-income countries. N Engl J Med. 2008, 358: 213-216. 10.1056/NEJMp0708307.CrossRefPubMed
2.
go back to reference Goldhirsch A, Glick JH, Gelber RD, Coates AS, Senn HJ: Meeting highlights: International Consensus Panel on the Treatment of Primary Breast Cancer. Seventh International Conference on Adjuvant Therapy of Primary Breast Cancer. J Clin Oncol. 2001, 19: 3817-3827.PubMed Goldhirsch A, Glick JH, Gelber RD, Coates AS, Senn HJ: Meeting highlights: International Consensus Panel on the Treatment of Primary Breast Cancer. Seventh International Conference on Adjuvant Therapy of Primary Breast Cancer. J Clin Oncol. 2001, 19: 3817-3827.PubMed
3.
go back to reference Ross JS, Fletcher JA, Linette GP, Stec J, Clark E, Ayers M, Symmans WF, Pusztai L, Bloom KJ: The Her-2/neu gene and protein in breast cancer 2003: biomarker and target of therapy. Oncologist. 2003, 8: 307-325. 10.1634/theoncologist.8-4-307.CrossRefPubMed Ross JS, Fletcher JA, Linette GP, Stec J, Clark E, Ayers M, Symmans WF, Pusztai L, Bloom KJ: The Her-2/neu gene and protein in breast cancer 2003: biomarker and target of therapy. Oncologist. 2003, 8: 307-325. 10.1634/theoncologist.8-4-307.CrossRefPubMed
4.
go back to reference Abd El-Rehim DM, Ball G, Pinder SE, Rakha E, Paish C, Robertson JF, Macmillan D, Blamey RW, Ellis IO: High-throughput protein expression analysis using tissue microarray technology of a large well-characterised series identifies biologically distinct classes of breast cancer confirming recent cDNA expression analyses. Int J Cancer. 2005, 116: 340-350. 10.1002/ijc.21004.CrossRefPubMed Abd El-Rehim DM, Ball G, Pinder SE, Rakha E, Paish C, Robertson JF, Macmillan D, Blamey RW, Ellis IO: High-throughput protein expression analysis using tissue microarray technology of a large well-characterised series identifies biologically distinct classes of breast cancer confirming recent cDNA expression analyses. Int J Cancer. 2005, 116: 340-350. 10.1002/ijc.21004.CrossRefPubMed
5.
go back to reference Gruvberger-Saal SK, Cunliffe HE, Carr KM, Hedenfalk IA: Microarrays in breast cancer research and clinical practice--the future lies ahead. Endocr Relat Cancer. 2006, 13: 1017-1031. 10.1677/erc.1.01246.CrossRefPubMed Gruvberger-Saal SK, Cunliffe HE, Carr KM, Hedenfalk IA: Microarrays in breast cancer research and clinical practice--the future lies ahead. Endocr Relat Cancer. 2006, 13: 1017-1031. 10.1677/erc.1.01246.CrossRefPubMed
6.
go back to reference Dowsett M, Dunbier AK: Emerging biomarkers and new understanding of traditional markers in personalized therapy for breast cancer. Clin Cancer Res. 2008, 14: 8019-8026. 10.1158/1078-0432.CCR-08-0974.CrossRefPubMed Dowsett M, Dunbier AK: Emerging biomarkers and new understanding of traditional markers in personalized therapy for breast cancer. Clin Cancer Res. 2008, 14: 8019-8026. 10.1158/1078-0432.CCR-08-0974.CrossRefPubMed
7.
go back to reference Lanz RB, McKenna NJ, Onate SA, Albrecht U, Wong J, Tsai SY, Tsai MJ, O'Malley BW: A steroid receptor coactivator, SRA, functions as an RNA and is present in an SRC-1 complex. Cell. 1999, 97: 17-27. 10.1016/S0092-8674(00)80711-4.CrossRefPubMed Lanz RB, McKenna NJ, Onate SA, Albrecht U, Wong J, Tsai SY, Tsai MJ, O'Malley BW: A steroid receptor coactivator, SRA, functions as an RNA and is present in an SRC-1 complex. Cell. 1999, 97: 17-27. 10.1016/S0092-8674(00)80711-4.CrossRefPubMed
8.
go back to reference Caretti G, Lei EP, Sartorelli V: The DEAD-box p68/p72 proteins and the noncoding RNA steroid receptor activator SRA: eclectic regulators of disparate biological functions. Cell Cycle. 2007, 6: 1172-1176.CrossRefPubMed Caretti G, Lei EP, Sartorelli V: The DEAD-box p68/p72 proteins and the noncoding RNA steroid receptor activator SRA: eclectic regulators of disparate biological functions. Cell Cycle. 2007, 6: 1172-1176.CrossRefPubMed
9.
go back to reference Colley SM, Iyer KR, Leedman PJ: The RNA coregulator SRA, its binding proteins and nuclear receptor signaling activity. IUBMB Life. 2008, 60: 159-164. 10.1002/iub.22.CrossRefPubMed Colley SM, Iyer KR, Leedman PJ: The RNA coregulator SRA, its binding proteins and nuclear receptor signaling activity. IUBMB Life. 2008, 60: 159-164. 10.1002/iub.22.CrossRefPubMed
10.
go back to reference Leygue E: Steroid Receptor RNA activator (SRA1): unusual bi-faceted gene products with suspected relevance to breast cancer. Nucl Recept Signal. 2007, 5: e006-PubMedPubMedCentral Leygue E: Steroid Receptor RNA activator (SRA1): unusual bi-faceted gene products with suspected relevance to breast cancer. Nucl Recept Signal. 2007, 5: e006-PubMedPubMedCentral
11.
go back to reference Hussein-Fikret S, Fuller PJ: Expression of nuclear receptor coregulators in ovarian stromal and epithelial tumours. Mol Cell Endocrinol. 2005, 229: 149-160. 10.1016/j.mce.2004.08.005.CrossRefPubMed Hussein-Fikret S, Fuller PJ: Expression of nuclear receptor coregulators in ovarian stromal and epithelial tumours. Mol Cell Endocrinol. 2005, 229: 149-160. 10.1016/j.mce.2004.08.005.CrossRefPubMed
12.
go back to reference Lanz RB, Chua SS, Barron N, Soder BM, DeMayo F, O'Malley BW: Steroid receptor RNA activator stimulates proliferation as well as apoptosis in vivo. Mol Cell Biol. 2003, 23: 7163-7176. 10.1128/MCB.23.20.7163-7176.2003.CrossRefPubMedPubMedCentral Lanz RB, Chua SS, Barron N, Soder BM, DeMayo F, O'Malley BW: Steroid receptor RNA activator stimulates proliferation as well as apoptosis in vivo. Mol Cell Biol. 2003, 23: 7163-7176. 10.1128/MCB.23.20.7163-7176.2003.CrossRefPubMedPubMedCentral
13.
go back to reference Leygue E, Dotzlaw H, Watson PH, Murphy LC: Expression of the steroid receptor RNA activator in human breast tumors. Cancer Res. 1999, 59: 4190-4193.PubMed Leygue E, Dotzlaw H, Watson PH, Murphy LC: Expression of the steroid receptor RNA activator in human breast tumors. Cancer Res. 1999, 59: 4190-4193.PubMed
14.
go back to reference Murphy LC, Simon SLR, Parkes A, Leygue E, Dotzlaw H, Snell L, Troup S, Adeyinka A, Watson PH: Altered expression of estrogen receptor coregulators during human breast tumorigenesis. Cancer Res. 2000, 60: 6266-6271.PubMed Murphy LC, Simon SLR, Parkes A, Leygue E, Dotzlaw H, Snell L, Troup S, Adeyinka A, Watson PH: Altered expression of estrogen receptor coregulators during human breast tumorigenesis. Cancer Res. 2000, 60: 6266-6271.PubMed
15.
go back to reference Chooniedass-Kothari S, Emberley E, Hamedani MK, Troup S, Wang X, Czosnek A, Hube F, Mutawe M, Watson PH, Leygue E: The steroid receptor RNA activator is the first functional RNA encoding a protein. Febs Letters. 2004, 566: 43-47. 10.1016/j.febslet.2004.03.104.CrossRefPubMed Chooniedass-Kothari S, Emberley E, Hamedani MK, Troup S, Wang X, Czosnek A, Hube F, Mutawe M, Watson PH, Leygue E: The steroid receptor RNA activator is the first functional RNA encoding a protein. Febs Letters. 2004, 566: 43-47. 10.1016/j.febslet.2004.03.104.CrossRefPubMed
16.
go back to reference Emberley E, Huang GJ, Hamedani MK, Czosnek A, Ali D, Grolla A, Lu B, Watson PH, Murphy LC, Leygue E: Identification of new human coding steroid receptor RNA activator isoforms. Biochemical and Biophysical Research Communications. 2003, 301: 509-515. 10.1016/S0006-291X(02)03070-X.CrossRefPubMed Emberley E, Huang GJ, Hamedani MK, Czosnek A, Ali D, Grolla A, Lu B, Watson PH, Murphy LC, Leygue E: Identification of new human coding steroid receptor RNA activator isoforms. Biochemical and Biophysical Research Communications. 2003, 301: 509-515. 10.1016/S0006-291X(02)03070-X.CrossRefPubMed
17.
go back to reference Hube F, Guo JM, Chooniedass-Kothari S, Cooper C, Hamedani MK, Dibrov AA, Blanchard AAA, Wang XM, Deng G, Myal Y, Leygue E: Alternative splicing of the first intron of the steroid receptor RNA activator (SRA) participates in the generation of coding and noncoding RNA isoforms in breast cancer cell lines. DNA and Cell Biology. 2006, 25: 418-428. 10.1089/dna.2006.25.418.CrossRefPubMed Hube F, Guo JM, Chooniedass-Kothari S, Cooper C, Hamedani MK, Dibrov AA, Blanchard AAA, Wang XM, Deng G, Myal Y, Leygue E: Alternative splicing of the first intron of the steroid receptor RNA activator (SRA) participates in the generation of coding and noncoding RNA isoforms in breast cancer cell lines. DNA and Cell Biology. 2006, 25: 418-428. 10.1089/dna.2006.25.418.CrossRefPubMed
18.
go back to reference Kawashima H, Takano H, Sugita S, Takahara Y, Sugimura K, Nakatani T: A novel steroid receptor co-activator protein (SRAP) as an alternative form of steroid receptor RNA-activator gene: expression in prostate cancer cells and enhancement of androgen receptor activity. Biochem J. 2003, 369: 163-171. 10.1042/BJ20020743.CrossRefPubMedPubMedCentral Kawashima H, Takano H, Sugita S, Takahara Y, Sugimura K, Nakatani T: A novel steroid receptor co-activator protein (SRAP) as an alternative form of steroid receptor RNA-activator gene: expression in prostate cancer cells and enhancement of androgen receptor activity. Biochem J. 2003, 369: 163-171. 10.1042/BJ20020743.CrossRefPubMedPubMedCentral
19.
go back to reference Kurisu T, Tanaka T, Ishii J, Matsumura K, Sugimura K, Nakatani T, Kawashima H: Expression and function of human steroid receptor RNA activator in prostate cancer cells: role of endogenous hSRA protein in androgen receptor mediated transcription. Prostate Cancer and Prostatic Diseases. 2006, 9: 173-178. 10.1038/sj.pcan.4500867.CrossRefPubMed Kurisu T, Tanaka T, Ishii J, Matsumura K, Sugimura K, Nakatani T, Kawashima H: Expression and function of human steroid receptor RNA activator in prostate cancer cells: role of endogenous hSRA protein in androgen receptor mediated transcription. Prostate Cancer and Prostatic Diseases. 2006, 9: 173-178. 10.1038/sj.pcan.4500867.CrossRefPubMed
20.
go back to reference Fuller-Pace FV: DExD/H box RNA helicases: multifunctional proteins with important roles in transcriptional regulation. Nucleic Acids Res. 2006, 34: 4206-4215. 10.1093/nar/gkl460.CrossRefPubMedPubMedCentral Fuller-Pace FV: DExD/H box RNA helicases: multifunctional proteins with important roles in transcriptional regulation. Nucleic Acids Res. 2006, 34: 4206-4215. 10.1093/nar/gkl460.CrossRefPubMedPubMedCentral
21.
go back to reference Jung SY, Malovannaya A, Wei J, O'Malley BW, Qin J: Proteomic Analysis of Steady-State Nuclear Hormone Receptor Coactivator Complexes. Mol Endocrinol. 2005, 19: 2451-2465. 10.1210/me.2004-0476.CrossRefPubMed Jung SY, Malovannaya A, Wei J, O'Malley BW, Qin J: Proteomic Analysis of Steady-State Nuclear Hormone Receptor Coactivator Complexes. Mol Endocrinol. 2005, 19: 2451-2465. 10.1210/me.2004-0476.CrossRefPubMed
22.
go back to reference Cooper C, Guo J, Yan Y, Chooniedass-Kothari S, Hube F, Hamedani MK, Murphy LC, Myal Y, Leygue E: Increasing the relative expression of endogenous non-coding Steroid Receptor RNA Activator (SRA) in human breast cancer cells using modified oligonucleotides. Nucleic Acids Res. 2009, 37: 4518-4531. 10.1093/nar/gkp441.CrossRefPubMedPubMedCentral Cooper C, Guo J, Yan Y, Chooniedass-Kothari S, Hube F, Hamedani MK, Murphy LC, Myal Y, Leygue E: Increasing the relative expression of endogenous non-coding Steroid Receptor RNA Activator (SRA) in human breast cancer cells using modified oligonucleotides. Nucleic Acids Res. 2009, 37: 4518-4531. 10.1093/nar/gkp441.CrossRefPubMedPubMedCentral
23.
go back to reference Miksicek RJ, Myal Y, Watson PH, Walker C, Murphy LC, Leygue E: Identification of a novel breast- and salivary gland-specific, mucin-like gene strongly expressed in normal and tumor human mammary epithelium. Cancer Res. 2002, 62: 2736-2740.PubMed Miksicek RJ, Myal Y, Watson PH, Walker C, Murphy LC, Leygue E: Identification of a novel breast- and salivary gland-specific, mucin-like gene strongly expressed in normal and tumor human mammary epithelium. Cancer Res. 2002, 62: 2736-2740.PubMed
24.
go back to reference Watson PH, Snell L, Parisien M: The NCIC-Manitoba Breast Tumor Bank: a resource for applied cancer research. CMAJ. 1996, 155: 281-283.PubMedPubMedCentral Watson PH, Snell L, Parisien M: The NCIC-Manitoba Breast Tumor Bank: a resource for applied cancer research. CMAJ. 1996, 155: 281-283.PubMedPubMedCentral
25.
go back to reference Skliris GP, Hube F, Gheorghiu I, Mutawe MM, Penner C, Watson PH, Murphy LC, Leygue E, Myal Y: Expression of small breast epithelial mucin (SBEM) protein in tissue microarrays (TMAs) of primary invasive breast cancers. Histopathology. 2008, 52: 355-369. 10.1111/j.1365-2559.2007.02955.x.CrossRefPubMedPubMedCentral Skliris GP, Hube F, Gheorghiu I, Mutawe MM, Penner C, Watson PH, Murphy LC, Leygue E, Myal Y: Expression of small breast epithelial mucin (SBEM) protein in tissue microarrays (TMAs) of primary invasive breast cancers. Histopathology. 2008, 52: 355-369. 10.1111/j.1365-2559.2007.02955.x.CrossRefPubMedPubMedCentral
26.
go back to reference Skliris GP, Leygue E, Curtis-Snell L, Watson PH, Murphy LC: Expression of oestrogen receptor-beta in oestrogen receptor-alpha negative human breast tumours. Br J Cancer. 2006, 95: 616-626. 10.1038/sj.bjc.6603295.CrossRefPubMedPubMedCentral Skliris GP, Leygue E, Curtis-Snell L, Watson PH, Murphy LC: Expression of oestrogen receptor-beta in oestrogen receptor-alpha negative human breast tumours. Br J Cancer. 2006, 95: 616-626. 10.1038/sj.bjc.6603295.CrossRefPubMedPubMedCentral
27.
go back to reference Elston CW, Ellis IO: Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology. 1991, 19: 403-410. 10.1111/j.1365-2559.1991.tb00229.x.CrossRefPubMed Elston CW, Ellis IO: Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology. 1991, 19: 403-410. 10.1111/j.1365-2559.1991.tb00229.x.CrossRefPubMed
28.
go back to reference Landis JR, Koch GG: The measurement of observer agreement for categorical data. Biometrics. 1977, 33: 159-174. 10.2307/2529310.CrossRefPubMed Landis JR, Koch GG: The measurement of observer agreement for categorical data. Biometrics. 1977, 33: 159-174. 10.2307/2529310.CrossRefPubMed
29.
go back to reference Lanz RB, Razani B, Goldberg AD, O'Malley BW: Distinct RNA motifs are important for coactivation of steroid hormone receptors by steroid receptor RNA activator (SRA). Proc Natl Acad Sci USA. 2002, 99: 16081-16086. 10.1073/pnas.192571399.CrossRefPubMedPubMedCentral Lanz RB, Razani B, Goldberg AD, O'Malley BW: Distinct RNA motifs are important for coactivation of steroid hormone receptors by steroid receptor RNA activator (SRA). Proc Natl Acad Sci USA. 2002, 99: 16081-16086. 10.1073/pnas.192571399.CrossRefPubMedPubMedCentral
30.
go back to reference Cooper C, Guo J, Yan Y, Chooniedass-Kothari S, Hube F, Hamedani MK, Murphy LC, Myal Y, Leygue E: Increasing the relative expression of endogenous non-coding Steroid Receptor RNA Activator (SRA) in human breast cancer cells using modified oligonucleotides. Nucleic Acids Res. 2009, 37: 4518-4531. 10.1093/nar/gkp441.CrossRefPubMedPubMedCentral Cooper C, Guo J, Yan Y, Chooniedass-Kothari S, Hube F, Hamedani MK, Murphy LC, Myal Y, Leygue E: Increasing the relative expression of endogenous non-coding Steroid Receptor RNA Activator (SRA) in human breast cancer cells using modified oligonucleotides. Nucleic Acids Res. 2009, 37: 4518-4531. 10.1093/nar/gkp441.CrossRefPubMedPubMedCentral
32.
go back to reference Zhao J: Sumoylation regulates diverse biological processes. Cell Mol Life Sci. 2007, 64: 3017-3033. 10.1007/s00018-007-7137-4.CrossRefPubMed Zhao J: Sumoylation regulates diverse biological processes. Cell Mol Life Sci. 2007, 64: 3017-3033. 10.1007/s00018-007-7137-4.CrossRefPubMed
33.
go back to reference Green A, Burney C, Granger C, Paish E, El-Sheikh S, Rakha E, Powe D, Macmillan R, Ellis I, Stylianou E: The prognostic significance of steroid receptor co-regulators in breast cancer: co-repressor NCOR2/SMRT is an independent indicator of poor outcome. Breast Cancer Research and Treatment. 2008, 110: 427-437. 10.1007/s10549-007-9737-y.CrossRefPubMed Green A, Burney C, Granger C, Paish E, El-Sheikh S, Rakha E, Powe D, Macmillan R, Ellis I, Stylianou E: The prognostic significance of steroid receptor co-regulators in breast cancer: co-repressor NCOR2/SMRT is an independent indicator of poor outcome. Breast Cancer Research and Treatment. 2008, 110: 427-437. 10.1007/s10549-007-9737-y.CrossRefPubMed
34.
go back to reference Camp RL, Chung GG, Rimm DL: Automated subcellular localization and quantification of protein expression in tissue microarrays. Nat Med. 2002, 8: 1323-1327. 10.1038/nm791.CrossRefPubMed Camp RL, Chung GG, Rimm DL: Automated subcellular localization and quantification of protein expression in tissue microarrays. Nat Med. 2002, 8: 1323-1327. 10.1038/nm791.CrossRefPubMed
35.
go back to reference Henderson KD, Bernstein L, Henderson B, Kolonel L, Pike MC: Predictors of the timing of natural menopause in the multiethnic cohort study. Am J Epidemiol. 2008, 167: 1287-1294. 10.1093/aje/kwn046.CrossRefPubMed Henderson KD, Bernstein L, Henderson B, Kolonel L, Pike MC: Predictors of the timing of natural menopause in the multiethnic cohort study. Am J Epidemiol. 2008, 167: 1287-1294. 10.1093/aje/kwn046.CrossRefPubMed
36.
go back to reference Menopause practice: a clinician's guide. 2007, The North American Menopause Society: Cleveland Menopause practice: a clinician's guide. 2007, The North American Menopause Society: Cleveland
Metadata
Title
Steroid Receptor RNA Activator Protein (SRAP): a potential new prognostic marker for estrogen receptor-positive/node-negative/younger breast cancer patients
Authors
Yi Yan
George P Skliris
Carla Penner
Shilpa Chooniedass-Kothari
Charlton Cooper
Zoann Nugent
Anne Blanchard
Peter H Watson
Yvonne Myal
Leigh C Murphy
Etienne Leygue
Publication date
01-10-2009
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 5/2009
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr2359

Other articles of this Issue 5/2009

Breast Cancer Research 5/2009 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine