Overexpression of folate binding protein and mesothelin are associated with uterine serous carcinoma.
OBJECTIVE
Folate receptor alpha (FOLR1) is a membrane bound receptor involved in the transport of folate as well as other regulatory cellular processes. The purpose of this study was to examine the expression of FOLR1 in uterine cancers and to identify changes in gene expression that are associated with overexpression of FOLR1.


METHODS
Fifty-eight frozen uterine cancer specimens were stained for FOLR1 using immunohistochemistry and results were correlated with transcript expression noted on quantitative PCR. Total RNA from 16 cases of uterine serous carcinoma (USC) was analyzed for gene expression using the Affymetrix HG-U133A and HG-U133B GeneChip set. USCs overexpressing FOLR1 were compared to cancers with an absence of FOLR1 using binary comparison and template matching of data was used to identify genes that correlate with FOLR1 expression. Selected targets from this analysis were evaluated by quantitative PCR as well as in an independent set of USC represented in quadruplicate on a tissue microarray (TMA).


RESULTS
Overexpression of FOLR1 was observed in 11/16 (69%) of USC and 0/10 normal endometrium cases using frozen tissue specimens. Binary comparison between FOLR1 positive and negative cases identified 121 genes altered by 2-fold at p<0.01 of which 45 are well correlated with FOLR1 expression pattern. Using quantitative PCR, both mesothelin (MSLN) and PTGS1 (COX1) were significantly increased in FOLR1 overexpressing tumors (p=0.014 and p=0.006 respectively). TMA confirmed that overexpression of FOLR1 and MSLN respectively occurred in 23/48 (48%) and 17/54 (32%) of pure USC.


CONCLUSIONS
Both FOLR1 and MSLN are cell surface targets that are co-expressed at high levels in USC and are appealing targets for biologic therapy.
Dainty
Louis A
LA
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology and the United States Military Cancer Institute, Walter Reed Army Medical Center, Washington, DC 20307, USA.
Risinger
John I
JI
Morrison
Carl
C
Chandramouli
G V R
GV
Bidus
Michael A
MA
Zahn
Chris
C
Rose
G Scott
GS
Fowler
Jeff
J
Berchuck
Andrew
A
Maxwell
G Larry
GL
D018269:Carcinoma, Endometrioid / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D018284:Cystadenocarcinoma, Serous / Q000235:genetics / Q000378:metabolism*; D005260:Female; D058975:Folate Receptor 1; D058973:Folate Receptors, GPI-Anchored; D058851:GPI-Linked Proteins; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D000090204:Mesothelin; D018200:Mixed Tumor, Mullerian / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000235:genetics; D014594:Uterine Neoplasms / Q000235:genetics / Q000378:metabolism*
D002352:Carrier Proteins; C548696:FOLR1 protein, human; D058975:Folate Receptor 1; D058973:Folate Receptors, GPI-Anchored; D058851:GPI-Linked Proteins; C000715527:MSLN protein, human; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D000090204:Mesothelin