High expression of folate receptor alpha in lung cancer correlates with adenocarcinoma histology and EGFR [corrected] mutation.
BACKGROUND
Folate receptor alpha (FRα) and reduced folate carrier-1 (RFC1) regulate uptake of folate molecules inside the cell. FRα is a potential biomarker of tumors response to antifolate chemotherapy, and a target for therapies using humanized monocloncal antibody. Information on the protein expression of these receptors in non-small-cell lung carcinoma (NSCLC) is limited.


METHODS
Expressions of FRα and RFC1 were examined by immunohistochemistry (IHC) in 320 surgically resected NSCLC (202 adenocarcinomas and 118 squamous cell carcinomas) tissue specimens and correlated with patients' clinico-pathologic characteristics. Folate receptor α gene (FOLR1) mRNA expression was examined using publicly available microarray datasets. FRα expression was correlated with thymidylate synthase and p53 expression in NSCLCs, and with epidermal growth factor receptor (EGFR) and V-Ki-ras2 Kirsten rat sarcoma viral (KRAS) gene mutations in adenocarcinomas.


RESULTS
NSCLC overexpressed FRα and RFC1. In a multivariate analysis, lung adenocarcinomas were more likely to express FRα in the cytoplasm (OR = 4.39; p < 0.0001) and membrane (OR = 5.34; p < 0.0001) of malignant cells than squamous cell carcinomas. Tumors from never-smokers were more likely to express cytoplasmic (OR = 3.35; p<0.03) and membrane (OR = 3.60; p=0.0005) FRα than those from smokers. In adenocarcinoma, EGFR mutations correlated with higher expression of membrane FRα and FOLR1 gene expressions. High levels of FRα expression was detected in 42 NSCLC advanced metastatic tumor tissues.


CONCLUSIONS
FRα and RFC1 proteins are overexpressed in NSCLC tumor tissues. The high levels of FRα in lung adenocarcinomas may be associated to these tumors' better responses to antifolate chemotherapy and represents a potential novel target for this tumor type.
Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Maria Ines
MI
Nunez
Carmen
C
Behrens
Denise M
DM
Woods
Heather
H
Lin
Milind
M
Suraokar
Humam
H
Kadara
Wayne
W
Hofstetter
Neda
N
Kalhor
J Jack
JJ
Lee
Wilbur
W
Franklin
David J
DJ
Stewart
Ignacio I
II
Wistuba
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D058975:Folate Receptor 1 / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D051818:Replication Protein C / Q000378:metabolism; D046888:Tissue Array Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
D058975:Folate Receptor 1; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C081632:RFC1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C512478:EGFR protein, human; D066246:ErbB Receptors; D051818:Replication Protein C; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins