Molecule Information

General Information of the Molecule (ID: Mol00035)

• Name: Breast cancer type 1 susceptibility protein (BRCA1) ,Homo sapiens
• Synonyms: RING finger protein 53; RING-type E3 ubiquitin transferase BRCA1; RNF53
• Molecule Type: Protein
• Gene Name: BRCA1
• Gene ID: 672
• Location: chr17:43044295-43170245[-]
• Sequence:
  MDLSALRVEEVQNVINAMQKILECPICLELIKEPVSTKCDHIFCKFCMLKLLNQKKGPSQ
  CPLCKNDITKRSLQESTRFSQLVEELLKIICAFQLDTGLEYANSYNFAKKENNSPEHLKD
  EVSIIQSMGYRNRAKRLLQSEPENPSLQETSLSVQLSNLGTVRTLRTKQRIQPQKTSVYI
  ELGSDSSEDTVNKATYCSVGDQELLQITPQGTRDEISLDSAKKAACEFSETDVTNTEHHQ
  PSNNDLNTTEKRAAERHPEKYQGSSVSNLHVEPCGTNTHASSLQHENSSLLLTKDRMNVE
  KAEFCNKSKQPGLARSQHNRWAGSKETCNDRRTPSTEKKVDLNADPLCERKEWNKQKLPC
  SENPRDTEDVPWITLNSSIQKVNEWFSRSDELLGSDDSHDGESESNAKVADVLDVLNEVD
  EYSGSSEKIDLLASDPHEALICKSERVHSKSVESNIEDKIFGKTYRKKASLPNLSHVTEN
  LIIGAFVTEPQIIQERPLTNKLKRKRRPTSGLHPEDFIKKADLAVQKTPEMINQGTNQTE
  QNGQVMNITNSGHENKTKGDSIQNEKNPNPIESLEKESAFKTKAEPISSSISNMELELNI
  HNSKAPKKNRLRRKSSTRHIHALELVVSRNLSPPNCTELQIDSCSSSEEIKKKKYNQMPV
  RHSRNLQLMEGKEPATGAKKSNKPNEQTSKRHDSDTFPELKLTNAPGSFTKCSNTSELKE
  FVNPSLPREEKEEKLETVKVSNNAEDPKDLMLSGERVLQTERSVESSSISLVPGTDYGTQ
  ESISLLEVSTLGKAKTEPNKCVSQCAAFENPKGLIHGCSKDNRNDTEGFKYPLGHEVNHS
  RETSIEMEESELDAQYLQNTFKVSKRQSFAPFSNPGNAEEECATFSAHSGSLKKQSPKVT
  FECEQKEENQGKNESNIKPVQTVNITAGFPVVGQKDKPVDNAKCSIKGGSRFCLSSQFRG
  NETGLITPNKHGLLQNPYRIPPLFPIKSFVKTKCKKNLLEENFEEHSMSPEREMGNENIP
  STVSTISRNNIRENVFKEASSSNINEVGSSTNEVGSSINEIGSSDENIQAELGRNRGPKL
  NAMLRLGVLQPEVYKQSLPGSNCKHPEIKKQEYEEVVQTVNTDFSPYLISDNLEQPMGSS
  HASQVCSETPDDLLDDGEIKEDTSFAENDIKESSAVFSKSVQKGELSRSPSPFTHTHLAQ
  GYRRGAKKLESSEENLSSEDEELPCFQHLLFGKVNNIPSQSTRHSTVATECLSKNTEENL
  LSLKNSLNDCSNQVILAKASQEHHLSEETKCSASLFSSQCSELEDLTANTNTQDPFLIGS
  SKQMRHQSESQGVGLSDKELVSDDEERGTGLEENNQEEQSMDSNLGEAASGCESETSVSE
  DCSGLSSQSDILTTQQRDTMQHNLIKLQQEMAELEAVLEQHGSQPSNSYPSIISDSSALE
  DLRNPEQSTSEKAVLTSQKSSEYPISQNPEGLSADKFEVSADSSTSKNKEPGVERSSPSK
  CPSLDDRWYMHSCSGSLQNRNYPSQEELIKVVDVEEQQLEESGPHDLTETSYLPRQDLEG
  TPYLESGISLFSDDPESDPSEDRAPESARVGNIPSSTSALKVPQLKVAESAQSPAAAHTT
  DTAGYNAMEESVSREKPELTASTERVNKRMSMVVSGLTPEEFMLVYKFARKHHITLTNLI
  TEETTHVVMKTDAEFVCERTLKYFLGIAGGKWVVSYFWVTQSIKERKMLNEHDFEVRGDV
  VNGRNHQGPKRARESQDRKIFRGLEICCYGPFTNMPTDQLEWMVQLCGASVVKELSSFTL
  GTGVHPIVVVQPDAWTEDNGFHAIGQMCEAPVVTREWVLDSVALYQCQELDTYLIPQIPH
  SHY
• Function: E3 ubiquitin-protein ligase that specifically mediates the formation of 'Lys-6'-linked polyubiquitin chains and plays a central role in DNA repair by facilitating cellular responses to DNA damage. It is unclear whether it also mediates the formation of other types of polyubiquitin chains. The BRCA1-BARD1 heterodimer coordinates a diverse range of cellular pathways such as DNA damage repair, ubiquitination and transcriptional regulation to maintain genomic stability. Regulates centrosomal microtubule nucleation. Required for appropriate cell cycle arrests after ionizing irradiation in both the S-phase and the G2 phase of the cell cycle. Required for FANCD2 targeting to sites of DNA damage. Inhibits lipid synthesis by binding to inactive phosphorylated ACACA and preventing its dephosphorylation. Contributes to homologous recombination repair (HRR) via its direct interaction with PALB2, fine-tunes recombinational repair partly through its modulatory role in the PALB2-dependent loading of BRCA2-RAD51 repair machinery at DNA breaks. Component of the BRCA1-RBBP8 complex which regulates CHEK1 activation and controls cell cycle G2/M checkpoints on DNA damage via BRCA1-mediated ubiquitination of RBBP8. Acts as a transcriptional activator.
• Uniprot ID: BRCA1_HUMAN
• Ensembl ID: ENSG00000012048
• HGNC ID: HGNC:1100

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 4 drug(s) in total

Cisplatin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [1]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: DNA damage repair signaling pathway; Inhibition; hsa03410
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: Hs-578T cells; Breast; Homo sapiens (Human); CVCL_0332
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Matrigel invasion assay
• Mechanism Description: miR-638 overexpression increased sensitivity to DNA-damaging agents, ultraviolet (UV) and cisplatin.

Disease Class: Ovarian cancer [2]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Homologous-recombination; Regulation
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: C13 cells; Ovary; Homo sapiens (Human); CVCL_0114
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunohistochemical staining assay
• Experiment for Drug Resistance: Tumor onset measured
• Mechanism Description: miR-9 bound directly to the 3'-UTR of BRCA1 and downregulated BRCA1 expression in ovarian cancer cells, miR-9 mediates the downregulation of BRCA1 and impedes DNA damage repair in ovarian cancer, improve chemotherapeutic (like cisplatin) efficacy by increasing the sensitivity of cancer cells to DNA damage.

Docetaxel

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [3]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Sensitive Drug: Docetaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: MCF-7/LCC2 cells; Breast; Homo sapiens (Human); CVCL_DP51
• In Vitro Model: MECs cells; Breast; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Enforced expression of hsa-miR125a-3p in breast cancer cells potentiates docetaxel sensitivity via modulation of BRCA1 signaling.

Olaparib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [4]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Sensitive Drug: Olaparib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vivo Model: CD1 nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: miR-182-mediated down-regulation of BRCA1 impedes DNA repair, and lead to Olaparib resistance.

Rucaparib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Ovarian cancer [5]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Rucaparib
• Molecule Alteration: Mutation; .
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: Here, we describe HRD mechanisms leading to both platinum and rucaparib sensitivity (BRCA mutation, RAD51C/D alterations, and high BRCA1 promoter methylation) and summarize two important cross-resistance mechanisms: BRCA reversion mutations, and loss of BRCA1 methylation described here for the first time using archival and screening clinical specimens.

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Ovarian cancer [6]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Rucaparib
• Molecule Alteration: Nonsense; p.R1443* (c.4327C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; .
• Mechanism Description: The nonsense p.R1443* (c.4327C>T) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway.

Disease Class: Ovarian cancer [6]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Rucaparib
• Molecule Alteration: Nonsense; p.Q1467* (c.4399C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; .
• Mechanism Description: The nonsense p.Q1467* (c.4399C>T) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway.

Disease Class: Ovarian cancer [6]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Rucaparib
• Molecule Alteration: Missense mutation; p.C61G (c.181T>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; .
• Mechanism Description: The missense mutation p.C61G (c.181T>G) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Disease Class: Ovarian cancer [6]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Rucaparib
• Molecule Alteration: Missense mutation; p.C64Y (c.191G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; .
• Mechanism Description: The missense mutation p.C64Y (c.191G>A) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Disease Class: Ovarian cancer [6]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Rucaparib
• Molecule Alteration: Missense mutation; p.M1V (c.1A>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; .
• Mechanism Description: The missense mutation p.M1V (c.1A>G) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Disease Class: Ovarian cancer [6]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Rucaparib
• Molecule Alteration: Missense mutation; p.R71G (c.211A>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; .
• Mechanism Description: The missense mutation p.R71G (c.211A>G) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Disease Class: Ovarian cancer [6]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Rucaparib
• Molecule Alteration: Missense mutation; p.R71K (c.212G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; .
• Mechanism Description: The missense mutation p.R71K (c.212G>A) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Disease Class: Ovarian cancer [6]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Rucaparib
• Molecule Alteration: Missense mutation; p.M1I (c.3G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; .
• Mechanism Description: The missense mutation p.M1I (c.3G>T) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Disease Class: Ovarian cancer [6]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Rucaparib
• Molecule Alteration: Missense mutation; p.R1495M (c.4484G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; .
• Mechanism Description: The missense mutation p.R1495M (c.4484G>T) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Disease Class: Ovarian cancer [6]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Rucaparib
• Molecule Alteration: Missense mutation; p.E1559K (c.4675G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; .
• Mechanism Description: The missense mutation p.E1559K (c.4675G>A) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Disease Class: Ovarian cancer [6]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Rucaparib
• Molecule Alteration: Missense mutation; p.D1692N (c.5074G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; .
• Mechanism Description: The missense mutation p.D1692N (c.5074G>A) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Breast cancer [ICD-11: 2C60]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Breast tissue
• The Specified Disease: Breast cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.05E-93; Fold-change: 5.27E-01; Z-score: 1.60E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 1.76E-19; Fold-change: 5.06E-01; Z-score: 1.86E+00

Ovarian cancer [ICD-11: 2C73]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Ovary
• The Specified Disease: Ovarian cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.11E-05; Fold-change: 6.78E-01; Z-score: 2.89E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 6.38E-01; Fold-change: 3.47E-01; Z-score: 3.36E-01

References

• Ref 1: miR-638 mediated regulation of BRCA1 affects DNA repair and sensitivity to UV and cisplatin in triple-negative breast cancer. Breast Cancer Res. 2014 Sep 17;16(5):435. doi: 10.1186/s13058-014-0435-5.
• Ref 2: miR-9 regulation of BRCA1 and ovarian cancer sensitivity to cisplatin and PARP inhibition. J Natl Cancer Inst. 2013 Nov 20;105(22):1750-8. doi: 10.1093/jnci/djt302. Epub 2013 Oct 29.
• Ref 3: Enforced expression of hsa-miR-125a-3p in breast cancer cells potentiates docetaxel sensitivity via modulation of BRCA1 signaling. Biochem Biophys Res Commun. 2016 Oct 28;479(4):893-900. doi: 10.1016/j.bbrc.2016.09.087. Epub 2016 Sep 28.
• Ref 4: miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors. Mol Cell. 2011 Jan 21;41(2):210-20. doi: 10.1016/j.molcel.2010.12.005. Epub 2010 Dec 30.
• Ref 5: Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (Parts 1 and 2) .Nat Commun. 2021 May 3;12(1):2487. doi: 10.1038/s41467-021-22582-6. 10.1038/s41467-021-22582-6
• Ref 6: Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trialLancet Oncol. 2017 Jan;18(1):75-87. doi: 10.1016/S1470-2045(16)30559-9. Epub 2016 Nov 29.