Specific changes in the proteomic pattern produced by the BRCA1-Ser1841Asn missense mutation.
BRCA1 is a nuclear phosphoprotein that plays a key role in many cell functions, including DNA repair, control of transcription, recombination and cell cycle homeostasis. Inherited missense mutations in the BRCA1 gene may predispose to breast and ovarian cancer, but the molecular mechanisms underlying BRCA1-induced tumorigenesis are still to be elucidated. Functional studies performed so far have contributed to the characterization of several single-nucleotide variants, mostly located at the BRCT domain, but very little is known about modifications in the protein pattern occurring in cells carrying these mutations. To shed more light in the molecular events triggered by missense mutations affecting breast cancer susceptibility genes, we have analyzed the whole cell proteome of stably transfected HeLa cell lines bearing three distinct single aminoacid changes in the BRCA1 protein (Ser1841Asn, Met1775Arg and Trp1837Arg) by means of liquid chromatography coupled to tandem-mass spectrometry. The results show that the Met1775Arg and the Trp1837Arg do not produce significant changes in the proteomic pattern compared to cells transfected with the wild-type BRCA1 cDNA. On the other hand, a different profile is detected in the BRCA1 Ser1841Asn-bearing cell line. In this particular subset, our attention has been focused on two proteins--the tumor protein D52 (TD52) and the folate receptor alpha (FOL1)--whose expression has been already reported to be upregulated in breast cancer, as well as in other tumors. Our findings indicate that Ser1841Asn BRCA1 mutation is able to activate specific protein pathways that are not triggered by other single aminoacid changes and pinpoint to the role TD52 and FOL1 as potential markers in breast cancer patients carrying this particular BRCA1 gene alteration.
Crugliano
Telma
T
Dipartimento di Medicina Sperimentale e Clinica "G. Salvatore", Università degli Studi di Catanzaro "Magna Graecia", Viale Europa Campus Universitario Germaneto, 88100 Catanzaro, Italy.
Quaresima
Barbara
B
Gaspari
Marco
M
Faniello
Maria Concetta
MC
Romeo
Francesco
F
Baudi
Francesco
F
Cuda
Giovanni
G
Costanzo
Francesco
F
Venuta
Salvatore
S
D019943:Amino Acid Substitution; D019313:BRCA1 Protein / Q000096:biosynthesis* / Q000235:genetics; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells; D006801:Humans; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism; D040901:Proteomics; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000235:genetics
D019313:BRCA1 Protein; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D009363:Neoplasm Proteins; D011956:Receptors, Cell Surface; C114751:TPD52 protein, human