Male breast cancer differs from female breast cancer in molecular features that affect prognoses and drug responses

•We comprehensively analyzed molecular differences between male breast cancer (MBC) and female breast cancer (FBC) after controlling for confounding factors with propensity score matching.•There are distinct differences in transcriptomes, genomes, immune microenvironments, epigenomes, proteomes, responses to sex hormones (estrogen and androgen), and drug sensitivities between MBC and FBC that underlie poor MBC prognoses.•The immunogenicity of MBC is lower than that of FBC and the efficacy of immunotherapy is worse.•The effect of estrogen on MBC is more intense, and anti-estrogen therapy is more important in treating MBC.•Differential expression of FDA-approved therapeutic target genes indicates that MBC differs from FBC in drug responses. Male breast cancer (MBC) is a rare malignancy with a worse prognosis than female breast cancer (FBC). Current MBC treatment strategies are based on those for FBC. However, molecular differences between MBC and FBC with respect to prognosis and drug responses remain unclear. After controlling for confounding factors with propensity score matching (PSM), differences between MBC and FBC were comprehensively analyzed using many types of data: survival, immune microenvironments, sex hormone responses, drug sensitivity, transcriptomes, genomes, epigenomes, and proteomes. Overall survival (OS) and cancer-specific survival (CSS) were both worse for MBC than for FBC. Differentially expressed mRNAs were enriched in numerous cancer-related functions and pathways, with SPAG16 and STOX1 being as the most important prognosis-related mRNAs for MBC. Competing endogenous RNA (ceRNA) and transcription factor (TF)-mRNA regulatory networks contain potential prognostic genes. Nine genes had higher mutation frequencies in MBC than in FBC. MBC shows a comparatively poor response to immunotherapy, with five proteins that promote breast cancer progression being highly expressed in MBC. MBC may be more responsive than FBC to estrogen. We detected six United States Food and Drug Administration (FDA)-approved therapeutic target genes as being differentially expressed between MBC and FBC. The poor prognosis of MBC compared to FBC is due to numerous molecular differences and resulting drug responses.