Breast cancer is the leading cause of cancer death among women worldwide. The vast majority of breast cancers are carcinomas that originate from cells lining the milk-forming ducts of the mammary gland.
The molecular subtypes of breast cancer, which are based on the presence or absence of hormone receptors (estrogen and progesterone subtypes) and human epidermal growth factor receptor-2 (HER2), include:
* Luminal A subtype: Hormone receptor positive (progesterone and estrogen) and HER2 (ERBB2) negative
* Luminal B subtype: Hormone receptor positive (progesterone and estrogen) and HER2 (ERBB2) positive
* HER2 positive: Hormone receptor negative (progesterone and estrogen) and HER2 (ERBB2) positive
* Basal-like or triple-negative (TNBCs): Hormone receptor negative (progesterone and estrogen) and HER2 (ERBB2) negative
Hormone receptor positive breast cancers are largely driven by the estrogen/ER pathway. In HER2 positive breast tumors, HER2 activates the PI3K/AKT and the RAS/RAF/MAPK pathways, and stimulate cell growth, survival and differentiation. In patients suffering from TNBC, the deregulation of various signaling pathways (Notch and Wnt/beta-catenin), EGFR protein have been confirmed. In the case of breast cancer only 8% of all cancers are hereditary, a phenomenon linked to genetic changes in BRCA1 or BRCA2. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at >10% incidence across all breast cancers. Phosphorylation sites were added based on information from PhosphoSitePlus (R), www.phosphosite.org.f7df14b21e1db88WHIM9 xenograft has activating mutation in KRASae4ee0fa2e06a02MOUSE:KG38 MOUSEfa2mutations: E542K or E545K in exon 9, and H1047R or H1047L in exon 20parent=P35222; parentsymbol=CTNNB1; site=QQQsyLDsGIHsGAT; position=ser33; sitegrpid=447487; ptm=p; direction=uparent=P35222; parent=CTNNB1; site=yLDsGIHsGATtTAP; position=ser37; sitegrpid=447582; ptm=p; direction=uparent=P35222; parent=CTNNB1; site=GIHsGATtTAPsLsG; position=thr41; sitegrpid=447583; ptm=p; direction=uparentid=Q02750; parentsymbol=MAP2K1; site=VsGQLIDsMANsFVG; position=ser218; sitegrpid=448514; ptm=p; direction=uparent=Q02750; parent=MAP2K1; site=LIDsMANsFVGtRSY; position=ser222; sitegrpid=448513; ptm=p; direction=uparentid=P28482; parentsymbol=MAPK1; site=HtGFLtEyVAtRWyr; position=tyr187; sitegrpid=447594; ptm=p; direction=uparentid=P28482; parentsymbol=MAPK1; site=HDHtGFLtEyVAtRW; position=thr185; sitegrpid=447593; ptm=p; direction=uparentid=P27361; parentsymbol=MAPK3; site=HDHtGFLtEyVAtRW; position=thr202; sitegrpid=447542; ptm=p; direction=uparentid=P27361; parentsymbol=MAPK3; site=HtGFLtEyVAtRWyr; position=tyr204; sitegrpid=447543; ptm=p; direction=uparentid=P36507; parentsymbol=MAP2K2; site=VsGQLIDsMANsFVG; position=ser222; sitegrpid=448073; ptm=p; direction=uparentid=P36507; parentsymbol=MAP2K2; site=LIDsMANsFVGtRSY; position=ser226; sitegrpid=448074; ptm=p; direction=udd720453058PubMedPredictive biomarkers of sensitivity to the phosphatidylinositol 3' kinase inhibitor GDC-0941 in breast cancer preclinical models.Clin Cancer Res2010O'Brien CWallin JJSampath DGuhaThakurta DSavage HPunnoose EAGuan JBerry LPrior WWAmler LCBelvin MFriedman LSLackner MR15805248PubMedPIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma.Cancer Res2005Saal LHHolm KMaurer MMemeo LSu TWang XYu JSMalmström POMansukhani MEnoksson JHibshoosh HBorg AParsons R27251275PubMedProteogenomics connects somatic mutations to signalling in breast cancer.Nature2016Mertins PMani DRRuggles KVGillette MAClauser KRWang PWang XQiao JWCao SPetralia FKawaler EMundt FKrug KTu ZLei JTGatza MLWilkerson MPerou CMYellapantula VHuang KLLin CMcLellan MDYan PDavies SRTownsend RRSkates SJWang JZhang BKinsinger CRMesri MRodriguez HDing LPaulovich AGFenyö DEllis MJCarr SAcancerDOID:162Disease17397528PubMedFGFR1 amplification in breast carcinomas: a chromogenic in situ hybridisation analysis.Breast Cancer Res2007Elbauomy Elsheikh SGreen ARLambros MBTurner NCGrainge MJPowe DEllis IOReis-Filho JS3798106PubMedHuman breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene.Science1987Slamon DJClark GMWong SGLevin WJUllrich AMcGuire WLphosphatidylinositol 3-kinase-Akt signaling pathwayPW:0000232Pathway Ontologycancer pathwayPW:0000605Pathway OntologyNotch signaling pathwayPW:0000204Pathway Ontology28348404PubMedProteogenomic integration reveals therapeutic targets in breast cancer xenografts.Nat Commun2017Huang KLLi SMertins PCao SGunawardena HPRuggles KVMani DRClauser KRTanioka MUsary JKavuri SMXie LYoon CQiao JWWrobel JWyczalkowski MAErdmann-Gilmore PSnider JEHoog JSingh PNiu BGuo ZSun SQSanati SKawaler EWang XScott AYe KMcLellan MDWendl MCMalovannaya AHeld JMGillette MAFenyö DKinsinger CRMesri MRodriguez HDavies SRPerou CMMa CReid Townsend RChen XCarr SAEllis MJDing L25514926PubMedPhosphoSitePlus, 2014: mutations, PTMs and recalibrations.Nucleic Acids Res2015Hornbeck PVZhang BMurray BKornhauser JMLatham VSkrzypek E20570901PubMedPotential for targeting the fibroblast growth factor receptors in breast cancer.Cancer Res2010Hynes NEDey JHdisease pathwayPW:0000013Pathway Ontology23220880PubMedActivating HER2 mutations in HER2 gene amplification negative breast cancer.Cancer Discov2013Bose RKavuri SMSearleman ACShen WShen DKoboldt DCMonsey JGoel NAronson ABLi SMa CXDing LMardis EREllis MJ18676830PubMedAn integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer.Cancer Res2008Stemke-Hale KGonzalez-Angulo AMLluch ANeve RMKuo WLDavies MCarey MHu ZGuan YSahin ASymmans WFPusztai LNolden LKHorlings HBerns KHung MCvan de Vijver MJValero VGray JWBernards RMills GBHennessy BTbreast cancer pathwayPW:0000624Pathway Ontology26028978PubMedPI3K mutations in breast cancer: prognostic and therapeutic implications.Breast Cancer (Dove Med Press)2015Mukohara T