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.