Supplementary Table 2A. Canonical pathways of genes down-regulated in SKBR3 cells by the combined treatment with rapamycin and doxorubicin SYMBOL GENES Role of BRCA1 in DNA damage BARD1, BLM, BRCA1, CHEK1, CHEK2, E2F6, FANCD2, , response/Hereditary breast cancer FANCM, HLTF, MLH1, PLH1, RAD51, RBBP8, RBL1, RFC2, RFC4, RFC5, CCNB1, CDC25C, CDK1, CHEK1, CHEK2, FANCD2, FANCL, HDC1, HLTF, POLR2D, RAD51, RPA1, SFN, TUBG1 Mitotic roles of polo-like kinase ANAPC7, ANAPC13, CCNB1, CDC7, CDC20, CDC23, CDC26, CDC27, CDC25A, CDC25C, CDK1, CHEK2, HSP90AA1, KIF11, KIF23, PLK1, PPP2RSE, PRC1, PTTG1 Cell cycle: G2/M DNA damage check BRCA1, CCNB1, CDC25C, CDK1, CHEK1, CHEK2, CKS2, point regulation CKS1B, PLK1, PRKDC, SFN, SKP2, TOP2A, YWHAG, YWHAQ Role of CHK proteins in cell cycle BRCA1, CDC25A, CDC25C, CDK1, CHEK1, CHEK2, E2F6, checkpoint controls PCNA, RAB17, RFC2, RFC4, RFC5, RPA1, Protein ubiquination pathway BAG1, BRCA1, CDC20, CDC23, DNAJC17, HSP90AA1, HSPA5, HSPA9, HSPA4L, HSPB11, HSPD1, HSPE1, HSPH1, PSMA7, PSMB3, PSMB6, PSMC1, PSMC5, PSMD1, PSMD2, PSMD3, PSMD11, PSMD12, PSMD13, PSMD14, SKP2, TCEB1, UBE2A, UBE2E2, UBE2G2, UBE2M, UBE25, UBE2V2, UCHL3, UCHL5, USP7, USP13, USP18, USP32 Purine metabolism ABCC6, ADK, AK2, ATP5B, ATP5G1, ATP5G3, ATP5J, BLM, DCK, DNA2, HLTF, HSPA5, HSPD1, IDE, KIF20B, LOC100132832, MLH1, MPP5, MPP6, NME1, NME7, NT5C3, NUDT9, PNP, PNPT1, POLA1, POLE2, POLH, POLR2D, PPAT, PSMC1, PSMC5, RFC5, RRM1, RRM2, VCP ATM signaling BID, BRCA1, CCNB1, CDC25A, CDC25C, CDK1, CHEK1, CHEK2, FANCD2, MAPK9, RAD51, SMC2, SMC3 Pyrimidine metabolism CTPS, DCK, DHODH, DKC1, DTYMK, DUT, NME1, NME7, NT5C3, PNP, PNPT1, POLAR1, POLE2, POLH, POLR2D, RFC5, RRM1, RRM2, TYMS, UCK2 DNA-double strand break repair by BRCA1, LIG1, POLA1, RAD51, RPA1 homologos recombination Ubiquinone biosynthesis COQ3, DNMT3B, NDUFA6, NDUFA8, NDUFA12, NDUFAB1, NDUFB6, NDUFC1, NDUFS1, NDUFS6, PRMT5 Glicine, serine, threonine DLD, ELOVL6, GARS, GLDC, GOT1, PHGDH, PISD, PLSB1, metabolism PSAT1, SHMT1, SHMT2 p53 signaling BIRC5, BRCA1, C12orf5, CHEK1, CHEK2, HDAC1, MED1, PCNA, PRKDC, SFN, STAG1, TOPBP1 Regulation of EIF4/P70S6K EIF2B5, EIF2S1, EIF3B, EIF4E, MAP2K1, PPP2R5E, EEF2K, signaling MAP2K1, PLCB1, PPP2R5E, SFN, YWHAG, YWHAQ PI3K/AKT signaling EIF4E, HSP90AA1, MAP2K1, PPP2R5E, RPS6KB2, SFN, THEM4, YWHAG, YWHAQ Mismatch repair EXO1, FEN1, MLH1, PCNA, RFC4, RFC5, RPA1 Lysine degradation ACAT2, ECHS1, ELOVL6, NSD1, PLOD2, SETD8, SHMT1, SHMT2, SUV39H2, WHSC1 Mitochondrial dysfunction AIFM1, ATP5B, ATP5J, DHODH, GLRX2, MAPK3, NDUFA6, NDUFA8, NDUFA12, NDUFAB1, NDUFB6, NDUFS1, NDFS6, PARK7, SDHA Cyclins and cell cycle regulation CCNA3, CCNA2, CCNB2, CCNH, CDC25A, CDK1, CDKN2C, E2F6, HDAC1, PPP2R5E, SKP2, TFDP1 14-3-3 mediated signaling MAP2K1, MAPK9, PLCB1, SNF, TUBA1B, TUBA1C, TUBA3C/TUBA, TUBA4A, TUBB, TUBB3, TUBB2C, TUBG1, YWHAG, YWHAQ Glycolysis AC4P1, ALDOC, BPGM, DHRS2, DLAT, DLD, GALM, HK1, LDHA, PDHX, PGAM1 Citrate cycle ACLY, ACO1, DLD, IDH3B, SDHA Underlined genes are those exclusively regulated by the combined treatment.

Supplementary Table 2B. Canonical pathways of genes up-regulated in SKBR3 cells by the combined treatment with rapamycin and doxorubicin SYMBOL GENES IL17a signaling in fibroblasts CCL12, CEBPD, IKB, IKBKE, JUN, NFKB1, NFKBIA, NFKBIE, NFKBIZ, TRAF3IP2 TNFRS signaling IKBKB, IKBKE, JUN, NFKB1, NFKBIA, NFKBIE, TNF, TNFAIP3 TNFR1 signaling IKBKB, IKBKE, JUN, NFKB1, NFKBIA, NFKBIE, PAK3, TNF, TNFAIP3, TRADD Role of PKR in interferon IKBKB, IKBKE, IRF1, NFKB1, NFKBIA, NFKBIE, TNF, induction TP53, TRAF3 CD40 signaling ICAM1, IKBKB, IKBKE, JUN, MAP2K5, NFKB1, NFKBIA, NFKBIE, PIK3CD, TNFAIP3, TRAF3 TWEAK signaling IKBKB, IKBKE, NFKB1, NFKBIA, NFKBIE, INFRSF25, TRADD, TRAF3 PPAR signaling CITED2, IKBKB, IKBKE, IL18, INSR, JUN, NFKB1, NFKBIA, NFKBIE, NR1H3, SCAND1, STAT5A, TNF Death receptor signaling HTRA2, IKBKB, IKBKE, NFKB1, NFKBIA, NFKBIE, TNF, TNFRSF21, TNFRSF25, TRADD IL17 signaling CCL2, CXCL1, CXCL10, CXCL11, IL8, JUN, NFKB1, NOS2, PIK3CD, TRAF31P2 TREM1 signaling CCL2, ICAM1, IL8, IL18, NFKB1, PLCG2, STAT5A, INF IL6 signaling CSNK2A2, IKBKB, IKBKE, IL8, IL18, JUN, NFBK1, NFKBIA, NFKBIE, TNF, TNFA1P6 IL10 signaling IKBKB, IKBKE, IL18, JUN, NFKB1, NFKBIA, NFKBIE, TNF NRF2 mediated oxidative stress ACTG1, AK7A2, CCS, DNAJB2, DNAJB12, FTH1, FTL, GSTK1, JUN, JUND, MAFF, MAFG, MAP2K5, PIK3CD, SQSTM1 NFKB signaling CSNK2A2, IKBKB, IL18, INSR, NFKB1, NFKBIA, NFKBIE, PIK3CD, PIK3CD, PLCG2, RELB, TNF, TNFAIP3, TN1P1, TRAF3 Apoptosis signaling HTRA2, IKBKB, IKBKE, NFKB1, NFKBIA, NFKBIE, PLCG2, TNF, TP53 P53 signaling ADCK3, BBC3, DRAM1, GADD45B, JUN, PIK3CD, THRS1, TP53 PI3K/AKT signaling GAB2, IKBKB, IKBKE, NFKB1, NFKBIA, NFKBIE, PIK3CD, PPP2R3B, TP53 RAR activation CITED2, CSNK2A2, JUN, NFKB1, PIK3CD, PRKAG1, RBP3, RPL71, SCAND1, SMAD3, SMAD6, STAT5A, TGFB2 Glycosaminglycan degradation GMDA, GNS, GUSB, HEXA, IDS, IDUA EIF2 signaling EIF3D, EIF3F, EIF3G, INSR, PABPC1, PIK3CD, PPP1R15A Cell cycle: G1/S checkpoint CDKN2B, HDAC4, HDAC11, SMAD3, TGFB2, TP53 regulation PI3K signaling in B lymphocytes BLNK, ATF3, IKBKB, IKBKE, JUN, NFKB1, NFKBIA, NFKBIE, PIK3CD, PLCG2 Underlined genes are those exclusively regulated by the combined treatment.