Here, we investigate therapy-induced senescence (TIS) as a reversible mechanism of drug resistance in breast cancer cells. High-dose doxorubicin treatment was used to induce TIS in four distinct breast cancer cell lines and the drug resistance/sensitivity pattern of parental and TIS cells were investigated using a panel of FDA-approved anticancer molecules. Proteome analysis confirmed the presence of the Senescence-Associated Secretory Phenotype (SASP), altered spliceosomal activity and proteins with significant role in immune evasion.