Abstract
Male breast cancer (MBC) is a poorly characterized disease because of its rarity. Clinical management is based on results obtained from randomized trials conducted in women notwithstanding data in the literature suggesting relevant gender-associated differences in terms of biological and clinical behavior. However, a genome-wide characterization of MBC on a transcriptional level is lacking. In this study, gene expression profiles of 37 estrogen receptor positive (ER+) MBC specimens were compared to that of 53 ER+ Female Breast Cancer (FBC) samples similar for clinical and patho-biological features. Almost 1000 genes were found differentially expressed (FDRÂ <Â 1%) between female and male patients and biological interpretation highlighted a gender-associated modulation of key biological processes ranging from energy metabolism to regulation of translation and matrix remodeling as well as immune system recruitment. Moreover, an analysis of genes correlated to steroid receptors and ERBB2 suggested a prominent role for the androgen receptor in MBC with a minor relevance for progesterone receptor and ERBB2, although, similarly to FBC, a genomic amplification could be observed. Our findings support the idea that breast cancer is a quite different disease in male and female patients and the underlying gender-related biological differences are likely to have clinical implications connected with different susceptibility to treatment.
This is a preview of subscription content, access via your institution.



References
Contractor KB, Kaur K, Rodrigues GS, Kulkarni DM, Singhal H (2008) Male breast cancer: is the scenario changing. World J Surg Oncol 6:58
Nahleh Z, Girnius S (2006) Male breast cancer: a gender issue. Nat Clin Pract Oncol 3:428–437
Willsher PC, Leach IH, Ellis IO, Bourke JB, Blamey RW, Robertson JF (1997) A comparison outcome of male breast cancer with female breast cancer. Am J Surg 173:185–188
Goss PE, Reid C, Pintilie M, Lim R, Miller N (1999) Male breast carcinoma: a review of 229 patients who presented to the Princess Margaret Hospital during 40 years: 1955–1996. Cancer 85:629–639
Munoz de Toro MM, Maffini MV, Kass L, Luque EH (1998) Proliferative activity and steroid hormone receptor status in male breast carcinoma. J Steroid Biochem Mol Biol 67:333–339
Curigliano G, Colleoni M, Renne G, Mazzarol G, Gennari R, Peruzzotti G, de Braud E, Robertson C, Maiorano E, Veronesi P, Nole F, Mandala M, Ferretti G, Viale G, Goldhirsch A (2002) Recognizing features that are dissimilar in male and female breast cancer: expression of p21Waf1 and p27Kip1 using an immunohistochemical assay. Ann Oncol 13:895–902
Bloom KJ, Govil H, Gattuso P, Reddy V, Francescatti D (2001) Status of HER-2 in male and female breast carcinoma. Am J Surg 182:389–392
Weber-Chappuis K, Bieri-Burger S, Hurlimann J (1996) Comparison of prognostic markers detected by immunohistochemistry in male and female breast carcinomas. Eur J Cancer 32A:1686–1692
Sotiriou C, Pusztai L (2009) Gene-expression signatures in breast cancer. N Engl J Med 360:790–800
Fassan M, Baffa R, Palazzo JP, Lloyd J, Crosariol M, Liu CG, Volinia S, Alder H, Rugge M, Croce CM, Rosenberg A (2009) MicroRNA expression profiling of male breast cancer. Breast Cancer Res 11:R58
Ronchi E, Granata G, Brivio M, Coradini D, Miodini P, Di Fronzo G (1986) A double-labeling assay for simultaneous estimation and characterization of estrogen and progesterone receptors using radioiodinated estradiol and tritiated Org 2058. Tumori 72:251–257
Cappelletti V, Gariboldi M, De Cecco L, Toffanin S, Reid JF, Lusa L, Bajetta E, Celio L, Greco M, Fabbri A, Pierotti MA, Daidone MG (2008) Patterns and changes in gene expression following neo-adjuvant anti-estrogen treatment in estrogen receptor-positive breast cancer. Endocr Relat Cancer 15:439–449
Tusher VG, Tibshirani R, Chu G (2001) Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA 98:5116–5121
Alexa A, Rahnenfuhrer J, Lengauer T (2006) Improved scoring of functional groups from gene expression data by decorrelating GO graph structure. Bioinformatics 22:1600–1607
Warburg O (1956) On respiratory impairment in cancer cells. Science 124:269–270
Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033
Putignani L, Raffa S, Pescosolido R, Aimati L, Signore F, Torrisi MR, Grammatico P (2008) Alteration of expression levels of the oxidative phosphorylation system (OXPHOS) in breast cancer cell mitochondria. Breast Cancer Res Treat 110:439–452
Sennoune SR, Luo D, Martinez-Zaguilan R (2004) Plasmalemmal vacuolar-type H+-ATPase in cancer biology. Cell Biochem Biophys 40:185–206
Neumann CA, Fang Q (2007) Are peroxiredoxins tumor suppressors? Curr Opin Pharmacol 7:375–380
Mieyal JJ, Gallogly MM, Qanungo S, Sabens EA, Shelton MD (2008) Molecular mechanisms and clinical implications of reversible protein S-glutathionylation. Antioxid Redox Signal 10:1941–1988
Graff JR, Konicek BW, Carter JH, Marcusson EG (2008) Targeting the eukaryotic translation initiation factor 4E for cancer therapy. Cancer Res 68:631–634
Mamane Y, Petroulakis E, LeBacquer O, Sonenberg N (2006) mTOR, translation initiation and cancer. Oncogene 25:6416–6422
Caraglia M, Budillon A, Vitale G, Lupoli G, Tagliaferri P, Abbruzzese A (2000) Modulation of molecular mechanisms involved in protein synthesis machinery as a new tool for the control of cell proliferation. Eur J Biochem 267:3919–3936
Perez-Martinez X, Funes S, Camacho-Villasana Y, Marjavaara S, Tavares-Carreon F, Shingu-Vazquez M (2008) Protein synthesis and assembly in mitochondrial disorders. Curr Top Med Chem 8:1335–1350
Hunt JT (2009) Discovery of ixabepilone. Mol Cancer Ther 8:275–281
Cigler T, Vahdat LT (2010) Eribulin mesylate for the treatment of breast cancer. Expert Opin Pharmacother 11:1587–1593
Etienne-Manneville S, Hall A (2002) Rho GTPases in cell biology. Nature 420:629–635
Vega FM, Ridley AJ (2008) Rho GTPases in cancer cell biology. FEBS Lett 582:2093–2101
Howlin J, Rosenkvist J, Andersson T (2008) TNK2 preserves epidermal growth factor receptor expression on the cell surface and enhances migration and invasion of human breast cancer cells. Breast Cancer Res 10:R36
Chia WJ, Tang BL (2009) Emerging roles for Rab family GTPases in human cancer. Biochim Biophys Acta 1795:110–116
Hashimoto S, Onodera Y, Hashimoto A, Tanaka M, Hamaguchi M, Yamada A, Sabe H (2004) Requirement for Arf6 in breast cancer invasive activities. Proc Natl Acad Sci USA 101:6647–6652
Rensen WM, Mangiacasale R, Ciciarello M, Lavia P (2008) The GTPase Ran: regulation of cell life and potential roles in cell transformation. Front Biosci 13:4097–4121
Kohrmann A, Kammerer U, Kapp M, Dietl J, Anacker J (2009) Expression of matrix metalloproteinases (MMPs) in primary human breast cancer and breast cancer cell lines: new findings and review of the literature. BMC Cancer 9:188
Helleman J, Jansen MP, Ruigrok-Ritstier K, van Staveren IL, Look MP, Meijer-van Gelder ME, Sieuwerts AM, Klijn JG, Sleijfer S, Foekens JA, Berns EM (2008) Association of an extracellular matrix gene cluster with breast cancer prognosis and endocrine therapy response. Clin Cancer Res 14:5555–5564
Finak G, Bertos N, Pepin F, Sadekova S, Souleimanova M, Zhao H, Chen H, Omeroglu G, Meterissian S, Omeroglu A, Hallett M, Park M (2008) Stromal gene expression predicts clinical outcome in breast cancer. Nat Med 14:518–527
Bosman FT, Stamenkovic I (2003) Functional structure and composition of the extracellular matrix. J Pathol 200:423–428
Coronella-Wood JA, Hersh EM (2003) Naturally occurring B-cell responses to breast cancer. Cancer Immunol Immunother 52:715–738
de Visser KE, Eichten A, Coussens LM (2006) Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 6:24–37
Schmidt M, Bohm D, von Torne C, Steiner E, Puhl A, Pilch H, Lehr HA, Hengstler JG, Kolbl H, Gehrmann M (2008) The humoral immune system has a key prognostic impact in node-negative breast cancer. Cancer Res 68:5405–5413
Rody A, Holtrich U, Pusztai L, Liedtke C, Gaetje R, Ruckhaeberle E, Solbach C, Hanker L, Ahr A, Metzler D, Engels K, Karn T, Kaufmann M (2009) T-cell metagene predicts a favorable prognosis in estrogen receptor-negative and HER2-positive breast cancers. Breast Cancer Res 11:R15
Materna V, Stege A, Surowiak P, Priebsch A, Lage H (2006) RNA interference-triggered reversal of ABCC2-dependent cisplatin resistance in human cancer cells. Biochem Biophys Res Commun 348:153–157
Weaver DA, Crawford EL, Warner KA, Elkhairi F, Khuder SA, Willey JC (2005) ABCC5, ERCC2, XPA and XRCC1 transcript abundance levels correlate with cisplatin chemoresistance in non-small cell lung cancer cell lines. Mol Cancer 4:18
He L, Vasiliou K, Nebert DW (2009) Analysis and update of the human solute carrier (SLC) gene superfamily. Hum Genomics 3:195–206
Britsch S (2007) The neuregulin-I/ErbB signaling system in development and disease. Adv Anat Embryol Cell Biol 190:1–65
Lengyel E, Prechtel D, Resau JH, Gauger K, Welk A, Lindemann K, Salanti G, Richter T, Knudsen B, Vande Woude GF, Harbeck N (2005) C-Met overexpression in node-positive breast cancer identifies patients with poor clinical outcome independent of Her2/neu. Int J Cancer 113:678–682
Harada N, Ohmori Y, Yamaji R, Higashimura Y, Okamoto K, Isohashi F, Nakano Y, Inui H (2008) ARA24/Ran enhances the androgen-dependent NH2- and COOH-terminal interaction of the androgen receptor. Biochem Biophys Res Commun 373:373–377
Kang HY, Yeh S, Fujimoto N, Chang C (1999) Cloning and characterization of human prostate coactivator ARA54, a novel protein that associates with the androgen receptor. J Biol Chem 274:8570–8576
Lee SR, Ramos SM, Ko A, Masiello D, Swanson KD, Lu ML, Balk SP (2002) AR and ER interaction with a p21-activated kinase (PAK6). Mol Endocrinol 16:85–99
Schrantz N, da Silva Correia J, Fowler B, Ge Q, Sun Z, Bokoch GM (2004) Mechanism of p21-activated kinase 6-mediated inhibition of androgen receptor signaling. J Biol Chem 279:1922–1931
Rudlowski C, Friedrichs N, Faridi A, Fuzesi L, Moll R, Bastert G, Rath W, Buttner R (2004) Her-2/neu gene amplification and protein expression in primary male breast cancer. Breast Cancer Res Treat 84:215–223
Fonseca RR, Tomas AR, Andre S, Soares J (2006) Evaluation of ERBB2 gene status and chromosome 17 anomalies in male breast cancer. Am J Surg Pathol 30:1292–1298
Chanrion M, Negre V, Fontaine H, Salvetat N, Bibeau F, Mac Grogan G, Mauriac L, Katsaros D, Molina F, Theillet C, Darbon JM (2008) A gene expression signature that can predict the recurrence of tamoxifen-treated primary breast cancer. Clin Cancer Res 14:1744–1752
Ross JS, Slodkowska EA, Symmans WF, Pusztai L, Ravdin PM, Hortobagyi GN (2009) The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist 14:320–368
Korde LA, Zujewski JA, Kamin L, Giordano S, Domchek S, Anderson WF, Bartlett JMS, Gelmon K, Nahleh Z, Bergh J, Cutuli B, Pruneri G, McCaskill-Stevens W, Gralow J, Hortobagyi G, Cardoso F (2010) Multidisciplinary meeting on male breast cancer: summary and research recommendations. J Clin Oncol 28:2114–2122
Acknowledgments
Supported in part by Associazione Italiana per la Ricerca sul Cancro (PIs, MA Pierotti and MG Daidone), Progetto Integrato Oncologia from the Italian Health Ministry (PI, MG Daidone), Alleanza Contro il Cancro (PI, MG Daidone).
Conflict of interest statement
The authors declared that they have no competing interests.
Author information
Authors and Affiliations
Corresponding authors
Electronic supplementary material
Below is the link to the electronic supplementary material.
10549_2010_1015_MOESM6_ESM.jpg
Clustering analysis with PgR associated genes. Using a set of clones differentially expressed between PgR+ and PgR− MBC samples, a hierarchical clustering analysis was performed on the MBC dataset itself (A) as well as on our FBC dataset (B) and on the Chanrion FBC dataset (C) samples. A sub-cluster containing 7/8 PgR− tumors was noticed in the clustering of MBC samples, while a quite random distribution of PgR− tumors was observed in FBC datasets (JPG 111 kb)
Rights and permissions
About this article
Cite this article
Callari, M., Cappelletti, V., De Cecco, L. et al. Gene expression analysis reveals a different transcriptomic landscape in female and male breast cancer. Breast Cancer Res Treat 127, 601–610 (2011). https://doi.org/10.1007/s10549-010-1015-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-010-1015-8