The polymeric immunoglobulin receptor (PIGR) mediates transport of IgA and IgM antibodies across mucosal and glandular epithelia. Several studies have utilized immunohistochemistry to demonstrate that PIGR expression varies in different types of lung carcinoma, and is down-regulated during tumor progression. We have previously shown in cultured tumor cell-lines that basal transcription of the PIGR gene is regulated by the transcription factors USF1, USF2 and AP2. To examine the mechanism by which PIGR expression is down-regulated in lung carcinoma, RNA was microdissected from formalin-fixed, paraffin-embedded lung carcinomas (14 adenocarcinomas and 8 squamous cell carcinomas). Levels of PIGR, USF1, USF2 and AP2-alpha mRNA were quantified by real-time reverse transcriptase-polymerase chain reaction and normalized to mRNA for the housekeeping gene GAPDH. PIGR mRNA levels were decreased in adenocarcinomas and squamous cell carcinomas relative to adjacent non-tumor tissue, and were inversely correlated with stage of differentiation. USF1 and USF2 mRNA levels were reduced in adenocarcinomas relative to non-tumor tissue, while AP2-alpha levels were elevated. Multivariate regression analysis demonstrated that reduced USF2 mRNA and increased AP2-alpha mRNA levels were predictive of down-regulated PIGR mRNA expression in the majority of adenocarcinomas and in moderately differentiated squamous cell carcinomas.