56 phase. It also enhances ER-mediated gene transcription and is especially overexpressed in ER positive female breast cancer [32]. CCND1 ampliﬁcation has been linked to ER positive tumors as well, although some did not ﬁnd such a correlation [18, 24, 33]. In the present study, we could not identify a correlation between CCND1 copy number gain or ampliﬁcation and ER status. A clear cut association between CCND1 ampliﬁcation and patients’ outcome in female breast cancer is lacking, but CCND1 ampliﬁcation may be associated with a poor prognosis, particularly in ER positive tumors [23, 24, 33–35]. In the present group of male breast cancers, tumors with CCND1 copy number gain tended to have a higher mean mitotic count compared to tumors without CCND1 ampliﬁcation, a ﬁnding which is in line with the encoding protein function. More impor- tantly, ampliﬁcation of CCND1 was the only single gene which correlated with poor survival and had additional prognostic value aside from tumor size, mitotic count, and histological grade using a Cox regression analysis. MTDH is involved in several signaling pathways and ampliﬁcation of MTDH promotes metastases, enhances chemo-resistance and is associated with poor outcome in female breast cancer patients [36]. In line with these ﬁndings in females, we demonstrated that male breast cancer with MTDH copy number gain showed a more aggressive phenotype with a high mitotic count and a high histological grade. However, no correlation with prognosis and MTDH copy number change was found in our group of male breast cancer and no correlation with lymph node metastasis was found either. The genes located on different amplicons on chromo- some 8p11 (FGFR1; 29 %, ADAM9; 39 % and IKBKB; 32 %) were also often gained. These genes have been correlated with ER positive female breast cancers [18]. Since most male breast cancer cases are ER positive (93 % in the present group), frequent copy number gain of these genes can be explained by the high ratio of ER positive tumors [8, 9]. Nevertheless, we could not conﬁrm the correlation between copy number gain or ampliﬁcation of these genes and ER positive tumors in male breast cancer. However, in view of the low rate of ER negative male breast cancers in the present study, these results need to be interpreted with care. It is important to note that FGFR1 ampliﬁcation enhances tamoxifen resistance, which is particularly clinically relevant in male breast cancer, as endocrine therapy is often indicated in these patients [5]. Since FGFR1 copy number gain and ampliﬁcation seems to be common in male breast cancer and is suitable for targeted therapy, this gene could be of further interest in male breast cancer [37]. ADAM9, which is important in cell adhesion and tumor cell invasion, has potential in male breast cancer as well, since this gene is often affected and could be used for targeted therapy [38, 39]. 123 Breast Cancer Res Treat (2012) 135:49–58 Among the other genes studied, copy number gain of MED1, PRDM14, and BIRC5 were associated with a high grade phenotype, indicating that these genes play a role in the development or progression of aggressive male breast cancer. Indeed MED1 copy number gain tends to correlate with poor survival. We could not conﬁrm the prognostic relevance of the other genes in male breast cancer patients. Comparison with 103 female breast cancers revealed differences in copy number change between male and female breast cancer in a variety of genes, pointing toward differences in carcinogenesis. In male breast cancer CCND1 and EGFR were more often gained than in the female breast cancer group. In the group of female breast cancers EMSY and CPD copy number gain were seen more often than in males. In line with a previous comparative genomic hybridization study, female breast cancer showed more frequent ampliﬁcation in a variety of genes, partic- ularly in TRAF4 and EMSY [14]. None of the genes studied were signiﬁcantly more often ampliﬁed in male breast cancer. Alongside gender speciﬁc differences between male and female breast cancers, differences in genetic predisposition may also inﬂuence the genetic proﬁle of these tumors. Approximately 10 % of men with breast cancer are known to have a genetic predisposition, and especially BRCA2 mutations seem to be important [7]. Differences in BRCA mutations status between male and female breast cancers would have implications for the genetic makeup of these tumors and deserves further investigation. In conclusion, copy number gain of the genes CCND1 (11q13), TRAF4 (17q11), CDC6 (17q21), and MTDH (8q22) is very common in male breast cancer ([40 %) and these genes probably play a role in male breast carcino- genesis. Tumors with copy number gain of one or more genes showed a highly malignant phenotype. Also MED1, PRDM14, MTDH, and BIRC5 seem to be important in the development or progression of high grade male breast cancer. Ampliﬁcation of CCND1 was the most important single gene as it correlated with poor survival and had prognostic value in addition to the classical clinicopatho- logical prognostic factors. Using unsupervised hierarchical clustering a distinctive group of male breast cancer tumors was identiﬁed with poor survival. Compared to female breast cancer CCND1 and EGFR were found to be more frequently ampliﬁed in male breast cancer, while in females EMSY and CPD were more often involved and more frequent ampliﬁcations of TRAF4 and EMSY were found. Our results point toward important differences in carcinogenesis between male and female breast cancer, emphasizing the importance in identifying speciﬁc bio- markers and therapeutic targets for male breast cancer. Conﬂict of interest The authors declare no conﬂict of interest.