Estrogen receptors [ERs (subtypes α and β)], classified as a nuclear receptor super family, are intracellular proteins with an important biological role as the transcription factors for estrogen target genes. For ER-induced transcription, an interaction must exist between ligand and coregulators. Coregulators may stimulate (coactivators) or inhibit (corepressors) transcription, following binding with a specific region of the gene, called the estrogen response element. Misbalanced activity of coregulators or higher ligand concentrations may cause increased cell proliferation, resulting in specific types of cancer. These are exhibited as overexpression of ER proteins. Breast cancer currently ranks first in the incidence and second in the mortality of cancer in females worldwide. In addition, 70% of breast tumors are ERα positive and the importance of these proteins for diagnostic use is indisputable. Early diagnosis of the tumor and its classification has a large influence on the selection of appropriate therapy, as ER-positive tumors demonstrate a positive response to hormonal therapy. Matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI TOF MS) has been hypothesized to have great potential, as it offers reliable, robust and efficient analysis methods for biomarker monitoring and identification. The present review discusses ER protein analysis by MALDI TOF MS, including the crucial step of protein separation.

Department of Chemistry and Biochemistry Faculty of Agronomy Mendel University in Brno Brno CZ 613 00 Czech Republic

Department of Chemistry and Biochemistry Faculty of Agronomy Mendel University in Brno Brno CZ 613 00 Czech Republic ; Central European Institute of Technology Brno University of Technology Brno CZ 616 00 Czech Republic

Department of Veterinary Ecology and Environmental Protection Faculty of Veterinary Hygiene and Ecology University of Veterinary and Pharmaceutical Sciences Brno Brno CZ 612 42 Czech Republic

Department of Veterinary Ecology and Environmental Protection Faculty of Veterinary Hygiene and Ecology University of Veterinary and Pharmaceutical Sciences Brno Brno CZ 612 42 Czech Republic ; Department of Chemistry and Biochemistry Faculty of Agronomy Mendel University in Brno Brno CZ 613 00 Czech Republic

Department of Veterinary Ecology and Environmental Protection Faculty of Veterinary Hygiene and Ecology University of Veterinary and Pharmaceutical Sciences Brno Brno CZ 612 42 Czech Republic ; Department of Chemistry and Biochemistry Faculty of Agronomy Mendel University in Brno Brno CZ 613 00 Czech Republic ; Central European Institute of Technology Brno University of Technology Brno CZ 616 00 Czech Republic

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Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90. PubMed

Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11–30. PubMed

Patani N, Martin LA, Dowsett M. Biomarkers for the clinical management of breast cancer: international perspective. Int J Cancer. 2013;133:1–13. PubMed

Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA. 2006;295:2492–2502. PubMed

Yang XR, Chang-Claude J, Goode EL, et al. Associations of breast cancer risk factors with tumor subtypes: a pooled analysis from the Breast Cancer Association Consortium studies. J Natl Cancer Inst. 2011;103:250–263. PubMed PMC

Muss HB. Coming of age: breast cancer in seniors. Oncologist. 2011;16(Suppl 1):S79–S87. PubMed

Ma H, Wang Y, Sullivan-Halley J, et al. Use of four biomarkers to evaluate the risk of breast cancer subtypes in the women’s contraceptive and reproductive experiences study. Cancer Res. 2010;70:575–587. PubMed PMC

Shubbar E, Helou K, Kovács A, et al. High levels of γ-glutamyl hydrolase (GGH) are associated with poor prognosis and unfavorable clinical outcomes in invasive breast cancer. BMC Cancer. 2013;13:47. PubMed PMC

Tian W, Chen J, He H, Deng Y. MicroRNAs and drug resistance of breast cancer: basic evidence and clinical applications. Clin Transl Oncol. 2013;15:335–342. PubMed

Ombra MN, Di Santi A, Abbondanza C, Migliaccio A, Avvedimento EV, Perillo B. Retinoic acid impairs estrogen signaling in breast cancer cells by interfering with activation of LSD1 via PKA. Biochim Biophys Acta. 2013;1829:480–486. PubMed

Fasching PA, Heusinger K, Haeberle L, et al. Ki67, chemotherapy response, and prognosis in breast cancer patients receiving neoadjuvant treatment. BMC Cancer. 2011;11:486. PubMed PMC

Sharan S, Nikhil K, Roy P. Effects of low dose treatment of tributyltin on the regulation of estrogen receptor functions in MCF-7 cells. Toxicol Appl Pharmacol. 2013;269:176–186. PubMed

Yan Y, Liu H, Wen H, et al. The novel estrogen receptor GPER regulates the migration and invasion of ovarian cancer cells. Mol Cell Biochem. 2013;378:1–7. PubMed

Oh Y, Chung KC. Zinc finger protein 131 inhibits estrogen signaling by suppressing estrogen receptor α homo-dimerization. Biochem Biophys Res Commun. 2013;430:400–405. PubMed

Komm BS, Mirkin S. Evolution of the tissue selective estrogen complex (TSEC) J Cell Physiol. 2013;228:1423–1427. PubMed

Cheng Q, Chang JT, Geradts J, et al. Amplification and high-level expression of heat shock protein 90 marks aggressive phenotypes of human epidermal growth factor receptor 2 negative breast cancer. Breast Cancer Res. 2012;14:R62. PubMed PMC

Coughlan N, Thillainadesan G, Andrews J, Isovic M, Torchia J. β-Estradiol-dependent activation of the JAK/STAT pathway requires p/CIP and CARM1. Biochim Biophys Acta-Mol Cell Res. 2013;1833:1463–1475. PubMed

Sengupta S, Obiorah I, Maximov PY, Curpan R, Jordan VC. Molecular mechanism of action of bisphenol and bisphenol A mediated by oestrogen receptor alpha in growth and apoptosis of breast cancer cells. Br J Pharmacol. 2013;169:167–178. PubMed PMC

Levin ER. Integration of the extranuclear and nuclear actions of estrogen. Mol Endocrinol. 2005;19:1951–1959. PubMed PMC

Pirman DA, Efuet E, Ding XP, et al. Changes in cancer cell metabolism revealed by direct sample analysis with MALDI mass spectrometry. PLoS One. 2013;8:e61379. PubMed PMC

Cornett DS, Reyzer ML, Chaurand P, Caprioli RM. MALDI imaging mass spectrometry: molecular snapshots of biochemical systems. Nat Methods. 2007;4:828–833. PubMed

Wang HS, Wu HM, Cheng BH, et al. Functional analyses of endometriosis-related polymorphisms in the estrogen synthesis and metabolism-related genes. PLoS One. 2012;7:e47374. PubMed PMC

Srinivasan S, Nwachukwu JC, Parent AA, et al. Ligand-binding dynamics rewire cellular signaling via estrogen receptor-α. Nat Chem Biol. 2013;9:326–332. PubMed PMC

Aust S, Horak P, Pils D, et al. The prognostic value of estrogen receptor beta and proline-, glutamic acid- and leucine-rich protein 1 (PELP1) expression in ovarian cancer. BMC Cancer. 2013;13:115. PubMed PMC

Borjesson AE, Farman HH, Engdahl C, et al. The role of activation functions 1 and 2 of estrogen receptor-α for the effects of estradiol and selective estrogen receptor modulators in male mice. J Bone Miner Res. 2013;28:1117–1126. PubMed PMC

Zeng H, Wu JC, Bedford MT, et al. A TR-FRET-based functional assay for screening activators of CARM1. Chembiochem. 2013;14:827–835. PubMed PMC

Meric-Bernstam F, Gutierrez-Barrera AM, Litton J, et al. Genotype in BRCA-associated breast cancers. Breast J. 2013;19:87–91. PubMed PMC

Jiang H, Teng R, Wang Q, et al. Transcriptional analysis of estrogen receptor alpha variant mRNAs in colorectal cancers and their matched normal colorectal tissues. J Steroid Biochem Mol Biol. 2008;112:20–24. PubMed

Wang J, Li J, Fang R, Xie S, Wang L, Xu C. Expression of ERα36 in gastric cancer samples and their matched normal tissues. Oncol Lett. 2012;3:172–175. PubMed PMC

Tu BB, Lin SL, Yan LY, Wang ZY, Sun QY, Qiao J. ER-α36, a novel variant of estrogen receptor α, is involved in EGFR-related carcinogenesis in endometrial cancer. Am J Obstet Gynecol. 2011;205:227.e1–e6. PubMed

Kammerer M, Gutzwiller S, Stauffer D, Delhon I, Seltenmeyer Y, Fournier B. Estrogen receptor α (ERα) and estrogen related receptor α (ERRα) are both transcriptional regulators of the Runx2-I isoform. Mol Cell Endocrinol. 2013;369:150–160. PubMed

Gamucci T, Vaccaro A, Ciancola F, et al. Recurrence risk in small, node-negative, early breast cancer: a multicenter retrospective analysis. J Cancer Res Clin Oncol. 2013;139:853–860. PubMed PMC

Althuis MD, Fergenbaum JH, Garcia-Closas M, Brinton LA, Madigan MP, Sherman ME. Etiology of hormone receptor-defined breast cancer: a systematic review of the literature. Cancer Epidemiol Biomarkers Prev. 2004;13:1558–1568. PubMed

Thrane S, Lykkesfeldt AE, Larsen MS, Sorensen BS, Yde CW. Estrogen receptor α is the major driving factor for growth in tamoxifen-resistant breast cancer and supported by HER/ERK signaling. Breast Cancer Res Treat. 2013;139:71–80. PubMed

Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med. 2010;363:1938–1948. PubMed

Ramirez-Ardila DE, Helmijr JC, Look MP, et al. Hotspot mutations in PIK3CA associate with first-line treatment outcome for aromatase inhibitors but not for tamoxifen. Breast Cancer Res Treat. 2013;139:39–49. PubMed

Hiscox S, Davies EL, Barrett-Lee P. Aromatase inhibitors in breast cancer. Maturitas. 2009;63:275–279. PubMed

Hodgkinson VC, Agarwal V, El Fadl D, et al. Pilot and feasibility study: comparative proteomic analysis by 2-DE MALDI TOF/TOF MS reveals 14-3-3 proteins as putative biomarkers of response to neoadjuvant chemotherapy in ER-positive breast cancer. J Proteomics. 2012;75:2745–2752. PubMed

Kim SI, Sohn J, Koo JS, Park SH, Park HS, Park BW. Molecular subtypes and tumor response to neoadjuvant chemotherapy in patients with locally advanced breast cancer. Oncology. 2010;79:324–330. PubMed

Haddock CL, Holtz B, Senzer N, Nemunaitis J. Applications of HPLC-MALDI-TOF MS/MS phosphoproteomic analysis in oncological clinical diagnostics. Curr Proteomics. 2011;8:153–167.

Tangjitgamol S, Tanvanich S, Srijaipracharoen S, Manusirivithaya S. Expression of estrogen receptor, progesterone receptor, and Her-2/neu in primary and extra-corporeal endometrial cancer. Histol Histopathol. 2013;28:787–794. PubMed

Alkner S, Bendahl PO, Grabau D, et al. The role of AIB1 and PAX2 in primary breast cancer: validation of AIB1 as a negative prognostic factor. Ann Oncol. 2013;24:1244–1252. PubMed

Seferina SC, Nap M, van den Berkmortel F, Wals J, Voogd AC, Tjan-Heijnen VC. Reliability of receptor assessment on core needle biopsy in breast cancer patients. Tumour Biol. 2013;34:987–994. PubMed

Wik E, Ræder MB, Krakstad C, et al. Lack of estrogen receptor-α is associated with epithelial-mesenchymal transition and PI3K alterations in endometrial carcinoma. Clin Cancer Res. 2013;19:1094–1105. PubMed

Kinsella MD, Birdsong GG, Siddiqui MT, Cohen C, Hanley KZ. Immunohistochemical detection of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 in formalin-fixed breast carcinoma cell block preparations: correlation of results to corresponding tissue block (needle core and excision) samples. Diagn Cytopathol. 2013;41:192–198. PubMed

Sang QX, Man YG, Sung YM, et al. Non-receptor tyrosine kinase 2 reaches its lowest expression levels in human breast cancer during regional nodal metastasis. Clin Exp Metastasis. 2012;29:143–153. PubMed PMC

Jin Y, Zhang X, Lu D, et al. Histopathological and proteomic analysis of hepatic tissue from adult male zebrafish exposed to 17β-estradiol. Environ Toxicol Pharmacol. 2010;29:91–95. PubMed

Pietrowska M, Marczak L, Polanska J, et al. Mass spectrometry-based serum proteome pattern analysis in molecular diagnostics of early stage breast cancer. J Transl Med. 2009;7:60. PubMed PMC

Bouchal P, Dvorakova M, Scherl A, Garbis SD, Nenutil R, Vojtesek B. Intact protein profiling in breast cancer biomarker discovery: protein identification issue and the solutions based on 3D protein separation, bottom-up and top-down mass spectrometry. Proteomics. 2013;13:1053–1058. PubMed

Nalvarte I, Schwend T, Gustafsson JA. Proteomics analysis of the estrogen receptor alpha receptosome. Mol Cell Proteomics. 2010;9:1411–1422. PubMed PMC

Atsriku C, Benz CC, Scott GK, Gibson BW, Baldwin MA. Quantification of cysteine oxidation in human estrogen receptor by mass spectrometry. Anal Chem. 2007;79:3083–3090. PubMed PMC

Cornett DS, Mobley JA, Dias EC, et al. A novel histology-directed strategy for MALDI-MS tissue profiling that improves throughput and cellular specificity in human breast cancer. Mol Cell Proteomics. 2006;5:1975–1983. PubMed

Kabbage M, Trimeche M, Bergaoui S, et al. Calreticulin expression in infiltrating ductal breast carcinomas: relationships with disease progression and humoral immune responses. Tumour Biol. 2013;34:1177–1188. PubMed

Castilla MÁ, Diaz-Martin J, Sarrió D, et al. MicroRNA-200 family modulation in distinct breast cancer phenotypes. PLoS One. 2012;7:e47709. PubMed PMC

Paramanik V, Thakur MK. Estrogen receptor β and its domains interact with casein kinase 2, phosphokinase C, and N-myristoylation sites of mitochondrial and nuclear proteins in mouse brain. J Biol Chem. 2012;287:22305–22316. PubMed PMC

Bovet C, Plet B, Ruff M, et al. Towards high-throughput identification of endocrine disrupting compounds with mass spectrometry. Toxicol In Vitro. 2009;23:704–709. PubMed

Collodoro M, Lemaire P, Eppe G, et al. Identification and quantification of concentration-dependent biomarkers in MCF-7/BOS cells exposed to 17β-estradiol by 2-D DIGE and label-free proteomics. J Proteomics. 2012;75:4555–4569. PubMed

Lai TC, Chou HC, Chen YW, et al. Secretomic and proteomic analysis of potential breast cancer markers by two-dimensional differential gel electrophoresis. J Proteome Res. 2010;9:1302–1322. PubMed

Obazee O, Justenhoven C, Winter S, et al. Confirmation of the reduction of hormone replacement therapy-related breast cancer risk for carriers of the HSD17B1_937_G variant. Breast Cancer Res Treat. 2013;138:543–548. PubMed