Overexpression of platelet-derived growth factor receptor alpha in breast cancer is associated with tumour progression.
BACKGROUND
Receptor tyrosine kinases have been extensively studied owing to their frequently abnormal activation in the development and progression of human cancers. Platelet-derived growth factor receptors (PDGFRs) are receptors with intrinsic tyrosine kinase activity that regulate several functions in normal cells and are widely expressed in a variety of malignancies. After the demonstration that gastrointestinal stromal tumours without c-Kit mutations harbour PDGFR-alpha-activating mutations and that PDGFR-alpha is also a therapeutic target for imatinib mesylate, the interest for this receptor has increased considerably. Because breast cancer is one of the most frequent neoplasias in women worldwide, and only one study has reported PDGFR-alpha expression in breast carcinomas, the aim of this work was to investigate the potential significance of PDGFR-alpha expression in invasive mammary carcinomas.


METHODS
We used immunohistochemistry to detect PDGFR-alpha overexpression on a series of 181 formalin-fixed paraffin-embedded invasive ductal breast carcinomas and in two breast cancer cell lines: MCF-7 and HS578T. We associated its expression with known prognostic factors and we also performed polymerase chain reaction-single-stranded conformational polymorphism and direct sequencing to screen for PDGFR-alpha mutations.


RESULTS
PDGFR-alpha expression was observed in 39.2% of the breast carcinomas and showed an association with lymph node metastasis (P = 0.0079), HER-2 expression (P = 0.0265) and Bcl2 expression (P = 0.0121). A correlation was also found with the expression of platelet-derived growth factor A (PDGF-A; P = 0.0194). The two cell lines tested did not express PDGFR-alpha. Screening for mutations revealed alterations in the PDGFR-alpha gene at the following locations: 2500A-->G, 2529T-->A and 2472C-->T in exon 18 and 1701G-->A in exon 12. We also found an intronic insertion IVS17-50insA at exon 18 in all sequenced cases. None of these genetic alterations was correlated with PDGFR-alpha expression. The cell lines did not reveal any alterations in the PDGFR-alpha gene sequence.


CONCLUSIONS
PDGFR-alpha is expressed in invasive breast carcinomas and is associated with biological aggressiveness. The genetic alterations described were not correlated with protein expression, but other mechanisms such as gene amplification or constitutive activation of a signalling pathway inducing this receptor could still sustain PDGFR-alpha as a potential therapeutic target.
Carvalho
Inês
I
IPATIMUP-Institute of Molecular Pathology and Immunology of Porto University, Porto, Portugal. icarvalho@ipatimup.pt
Milanezi
Fernanda
F
Martins
Albino
A
Reis
Rui M
RM
Schmitt
Fernando
F
D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D017931:DNA Primers; D018450:Disease Progression; D005091:Exons; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics; D006580:Genetic Carrier Screening; D006720:Homozygote; D006801:Humans; D007438:Introns; D009154:Mutation; D009361:Neoplasm Invasiveness; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics*
D017931:DNA Primers; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta