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This version published online on February 7, 2006
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-2156
A more recent version of this article appeared on April 1, 2006
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Submitted on September 29, 2005
Accepted on January 26, 2006

A common polymorphism renders the Luteinizing Hormone receptor protein more active by improving signal peptide function and predicts adverse outcome in breast cancer patients

Djura Piersma, Els M.J.J. Berns, Miriam Verhoef-Post, Andre G. Uitterlinden, Ineke Braakman, Huibert A.P. Pols, and Axel P.N. Themmen*

Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands; Department of Medical Oncology, Erasmus MC, Rotterdam, The Netherlands; Department of Epidemiology & Biostatistics, Erasmus MC, Rotterdam, The Netherlands; Department of Clinical Chemistry, Erasmus MC, Rotterdam, The Netherlands; Department of Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, The Netherlands

* To whom correspondence should be addressed. E-mail: a.themmen{at}erasmusmc.nl.

Context: Epidemiological and animal studies indicate a carcinogenic role of estrogens in breast tissue. The pituitary gonadotropin Luteinizing Hormone (LH) is an important regulator of estrogen production in premenopausal women, whereas even in women after menopause 10 to 25% of ovarian steroid hormone production is LH-dependent.

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

Design: 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 clinico-pathological features was studied in a large cohort of 751 breast cancer patients with complete follow-up. Functional analysis of the insLQ-LHR and nonLQ-LHR (no LQ insertion) was carried out using transfection studies.

Results: We found a significant association between the insLQ-LHR and a shorter DFS (HR 1.34; CI 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 1.7 lower EC50 than nonLQ-LHR; P = 0.02) and plasma membrane expression (insLQ-LHR has 1.4 higher Bmax; P = 0.0006) rendering the insLQ-LHR allele more active.

Conclusions: The insLQ polymorphism increases LHR activity, thereby shortening breast cancer DFS, probably by increasing estrogen exposure in female carriers.




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