High expression of folate receptor alpha in lung cancer correlates with adenocarcinoma histology and mutation

Maria Ines Nunez, Carmen Behrens, Denise M. Woods, Heather Lin, Milind Suraokar, Humam Kadara, Wayne Hofstetter, Neda Kalhor, J. Jack Lee, Wilbur Franklin, David J. Stewart, Ignacio I. Wistuba

Research output: Contribution to journalReview articlepeer-review

86 Scopus citations


Introduction: 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. Material and 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 . 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.

Original languageEnglish (US)
Pages (from-to)833-840
Number of pages8
JournalJournal of Thoracic Oncology
Issue number5
StatePublished - 2012


  • Epidermal growth factor receptor
  • Folate receptor alpha
  • Membrane transporter
  • Non-small-cell lung carcinoma
  • Reduced folate carrier-1

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

MD Anderson CCSG core facilities

  • Biostatistics Resource Group
  • Tissue Biospecimen and Pathology Resource
  • Clinical Trials Office


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