A common polymorphism renders the luteinizing hormone receptor protein more active by improving signal peptide function and predicts adverse outcome in breast cancer patients.
BACKGROUND
Epidemiological and animal studies indicate a carcinogenic role of estrogens in breast tissue. The pituitary gonadotropin LH is an important regulator of estrogen production in premenopausal women, whereas even in women after menopause, 10-25% of ovarian steroid hormone production is LH dependent.


OBJECTIVE
We hypothesized that an LH receptor (LHR) gene variant may affect LHR function and thereby influence disease outcome in breast cancer patients.


METHODS
The association of a polymorphic CTCCAG (Leu-Gln) insertion (insLQ), in the signal peptide encoded by exon 1 of the LHR gene with breast cancer risk, (disease-free) survival, and clinicopathological features was studied in a large cohort of 751 breast cancer patients with complete follow-up. Functional analysis of the insLQ-LHR and non-LQ-LHR (no LQ insertion) was carried out using transfection studies.


RESULTS
We found a significant association between the insLQ-LHR and a shorter disease-free survival (hazard ratio, 1.34; confidence interval, 1.11-1.63; P = 0.003). The mechanism of the effect of insLQ on LHR function involves increased receptor sensitivity (insLQ-LHR has a 1.9 times lower EC(50) than non-LQ-LHR; P = 0.02) and plasma membrane expression (insLQ-LHR has 1.4 times higher B(max); P = 0.0006) rendering the insLQ-LHR allele more active.


CONCLUSIONS
The insLQ polymorphism increases LHR activity, thereby shortening breast cancer disease-free survival, probably by increasing estrogen exposure in female carriers.
Piersma
Djura
D
Department of Internal Medicine, Erasmus MC, Room Ee532, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.
Berns
Els M J J
EM
Verhoef-Post
Miriam
M
Uitterlinden
Andre G
AG
Braakman
Ineke
I
Pols
Huibert A P
HA
Themmen
Axel P N
AP
D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000628:therapy*; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D008875:Middle Aged; D009154:Mutation / Q000235:genetics / Q000502:physiology; D011110:Polymorphism, Genetic; D021381:Protein Transport / Q000502:physiology; D011974:Receptors, LH / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D013534:Survival; D014162:Transfection; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D018076:DNA, Complementary; D004273:DNA, Neoplasm; D008565:Membrane Proteins; D011974:Receptors, LH