The transcription functions of oestrogen receptors (ER) are influenced by several coregulators such as PELP1 (proline, glutamate and leucine rich protein 1). The aim of the present study, which uses tissue microarrays and immunohistochemistry, is to explore the clinical and biological relevance of PELP1 protein expression in a large series of consecutive patients (1,162 patients) with invasive breast cancers with particular emphasis on its role in the ER-positive/luminal-like class of tumours. Our results showed that increased PELP1 expression is associated with tumours of larger size, higher histological grade, higher mitotic count, and with positive expression of basal cytokeratins (CK) (CK14; P = 0.018 and CK5/6; P = 0.029), P-cadherin (P = 0.002), p53 and MIB1 (P = 0.018). There was an inverse association between PELP1 expression and ER (P = 0.002), progesterone (PgR) (P = 0.004), androgen (AR) receptor (P < 0.001), and luminal CK (CK18; P = 0.027) expression. A significant association between PELP1 expression and shorter breast cancer specific survival (BCSS) (P = 0.002) and disease-free survival (DFI) (P = 0.006) was found. Multivariate Cox hazard analysis showed that PELP1 expression was an independent predictor of shorter BCSS (Hazard ratio (HR) = 1.349, P = 0.006) and shorter DFI (HR = 1.255, P = 0.011). In the ER-positive/luminal-like group (n = 768), PELP1 expression showed similar association with other clinicopathological variables and was an independent predictor of shorter DFI (HR = 1.256, P = 0.036). In conclusion, PELP1 protein expression is an independent prognostic predictor of shorter BCSS and DFI in breast cancer and its elevated expression is positively associated with markers of poor outcome. PELP1 appears to have a potential application in assessing the clinical outcome of patients with ER-positive breast cancer.
Breast carcinoma PELP1 Oestrogen receptor Prognosis Immunohistochemistry Tissue microarray
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We thank the Ministry of Higher Education (Egypt) for funding H. O. Habashy and E. A. Rakha and Breast Cancer Campaign for funding A Green.
Vadlamudi RK, Wang RA, Mazumdar A, Kim Y, Shin J, Sahin A et al (2001) Molecular cloning and characterization of PELP1, a novel human coregulator of estrogen receptor alpha. J Biol Chem 276:38272–38279PubMedGoogle Scholar
Rajhans R, Nair HB, Nair SS, Cortez V, Ikuko K, Kirma NB et al (2008) Modulation of in situ estrogen synthesis by proline-, glutamic acid-, and leucine-rich protein-1: potential estrogen receptor autocrine signaling loop in breast cancer cells. Mol Endocrinol 22:649–664. doi:10.1210/me.2007-0350CrossRefPubMedGoogle Scholar
Rajhans R, Nair S, Holden AH, Kumar R, Tekmal RR, Vadlamudi RK (2007) Oncogenic potential of the nuclear receptor coregulator proline-, glutamic acid-, leucine-rich protein 1/modulator of the nongenomic actions of the estrogen receptor. Cancer Res 67:5505–5512. doi:10.1158/0008-5472.can-06-3647CrossRefPubMedGoogle Scholar
Tzelepi V, Grivas P, Kefalopoulou Z, Kalofonos H, Varakis J, Sotiropoulou-Bonikou G (2009) Expression of estrogen receptor co-regulators NCoR and PELP1 in epithelial cells and myofibroblasts of colorectal carcinomas: cytoplasmic translocation of NCoR in epithelial cells correlates with worse prognosis. Virchows Arch 454(1):41–53. doi:10.1007/s00428-008-0708-4CrossRefPubMedGoogle Scholar
Abd El-Rehim DM, Ball G, Pinder SE, Rakha E, Paish C, Robertson JFR et al (2005) 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 116:340–350. doi:10.1002/ijc.21004CrossRefPubMedGoogle Scholar
Habashy HO, Powe DG, Staka CM, Rakha EA, Ball G, Green AR et al (2009) Transferrin receptor (CD71) is a marker of poor prognosis in breast cancer and can predict response to tamoxifen. Breast Cancer ResTreat. doi:10.1007/s10549-009-0345-xGoogle Scholar
McCarty KS, Miller LS, Cox EB, Konrath J, McCarty KS (1985) Estrogen-receptor analyses—correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies. Arch Pathol Lab Med 109:716–721PubMedGoogle Scholar
Naderi A, Teschendorff AE, Barbosa-Morais NL, Pinder SE, Green AR, Powe DG et al (2006) A gene-expression signature to predict survival in breast cancer across independent data sets. Oncogene 26:1507–1516. doi:10.1038/sj.onc.1209920CrossRefPubMedGoogle Scholar
Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98:10869–10874. doi:10.1073/pnas.191367098CrossRefPubMedGoogle Scholar
Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A et al (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 100:8418–8423. doi:10.1073/pnas.0932692100CrossRefPubMedGoogle Scholar
Sotiriou C, Neo SY, McShane LM, Korn EL, Long PM, Jazaeri A et al (2003) Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci USA 100:10393–10398. doi:10.1073/pnas.1732912100CrossRefPubMedGoogle Scholar
West M, Blanchette C, Dressman H, Huang E, Ishida S, Spang R et al (2001) Predicting the clinical status of human breast cancer by using gene expression profiles. Proc Natl Acad Sci USA 98:11462–11467. doi:10.1073/pnas.201162998CrossRefPubMedGoogle Scholar
Nair S, Vadlamudi RK (2007) Emerging significance of ER-coregulator PELP1/MNAR in cancer. Histol Histopathol 22:91–96PubMedGoogle Scholar
Stallcup MR, Kim JH, Teyssier C, Lee Y-H, Ma H, Chen D (2003) The roles of protein-protein interactions and protein methylation in transcriptional activation by nuclear receptors and their coactivators. J Steroid Biochem Mol Biol 85:139–145. doi:10.1016/S0960-0760(03)00222-XCrossRefPubMedGoogle Scholar
Schiff R, Massarweh S, Shou J, Bharwani L, Arpino G, Rimawi M et al (2005) Advanced concepts in estrogen receptor biology and breast cancer endocrine resistance: implicated role of growth factor signaling and estrogen receptor coregulators. Cancer Chemother Pharmacol 56:10–20. doi:10.1007/s00280-005-0108-2CrossRefPubMedGoogle Scholar