Parathyroid hormone-related protein varies with sex and androgen status in nonsmall cell lung cancer.
BACKGROUND
In nonsmall cell lung cancer, tumor parathyroid hormone-related protein (PTHrP) expression predicts longer survival in women but not in men. To explain the sex-dependent survival effect, the authors proposed that hormonal influences decrease PTHrP in men versus women, that PTHrP inhibits tumor growth, and that the effect is greater in women than in men. The objectives of this study were to compare lung carcinoma PTHrP expression and carcinoma growth in male and female mice and to determine whether gonadal steroids regulate PTHrP in lung cancer cells.


METHODS
Tumor PTHrP content was measured by immunoassay, and tumor burden was assessed with multiple measures in BEN squamous cell orthotopic lung carcinomas in athymic mice. In addition, lung adenocarcinoma PTHrP messenger RNA (mRNA) values determined by microarray analyses were compared between men and women. Cultured lung cancer cells were assayed for PTHrP after treatment with estradiol or R1881, a synthetic androgen.


RESULTS
Lung carcinomas contained approximately 3 times more PTHrP in female mice than in male mice. Similarly, levels of PTHrP mRNA were significantly greater in adenocarcinomas from patients who were women than from patients who were men. Male mice had greater tumor burden than female mice. Androgen treatment reduced PTHrP in 3 lung cancer lines. Estradiol had no effect. Testosterone treatment also reduced lung carcinoma PTHrP in female mice.


CONCLUSIONS
Lung carcinomas in females expressed more PTHrP than in males possibly because of negative regulation by androgens in males. Female mice with higher tumor PTHrP content had significantly less tumor burden than male mice, supporting the hypothesis that PTHrP inhibits tumor growth.
Medicine Service, Veterans Affairs San Diego Healthcare System, San Diego, California, USA.
Philippe R
PR
Montgrain
Rick
R
Quintana
Yvette
Y
Rascon
Douglas W
DW
Burton
Leonard J
LJ
Deftos
Andrea
A
Casillas
Randolph H
RH
Hastings
D000230:Adenocarcinoma / Q000378:metabolism; D000728:Androgens / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D018287:Carcinoma, Large Cell / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D044162:Parathyroid Hormone-Related Protein / Q000097:blood / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012737:Sex Factors; D047368:Tumor Burden
D000728:Androgens; D012739:Gonadal Steroid Hormones; D044162:Parathyroid Hormone-Related Protein