This Article Full Text Full Text (PDF) All Versions of this Article: 91/4/1470    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Piersma, D. Articles by Themmen, A. P. N. Search for Related Content PubMed PubMed Citation Articles by Piersma, D. Articles by Themmen, A. P. N. Related Collections Endocrine Oncology Female Endocrinology

A Common Polymorphism Renders the Luteinizing Hormone Receptor Protein More Active by Improving Signal Peptide Function and Predicts Adverse Outcome in Breast Cancer Patients

Departments of Internal Medicine (D.P., M.V.-P., A.G.U., H.A.P.P., A.P.N.T.), Medical Oncology (E.M.J.J.B.), Epidemiology and Biostatistics (A.G.U., H.A.P.P.), and Clinical Chemistry (A.G.U.), Erasmus MC, 3000 DR Rotterdam, The Netherlands; and Department of Cellular Protein Chemistry (I.B.), Bijvoet Center for Biomolecular Research, Utrecht University, 3584 CH Utrecht, The Netherlands

Address all correspondence and requests for reprints to: Axel P. N. Themmen, Department of Internal Medicine, Erasmus MC, Room Ee532, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. E-mail: a.themmen{at}erasmusmc.nl.

Context: 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.

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 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 EC₅₀ 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.

This article has been cited by other articles:

				M. Bruysters, S. Christin-Maitre, M. Verhoef-Post, C. Sultan, J. Auger, I. Faugeron, L. Larue, S. Lumbroso, A.P.N. Themmen, and P. Bouchard A new LH receptor splice mutation responsible for male hypogonadism with subnormal sperm production in the propositus, and infertility with regular cycles in an affected sister Hum. Reprod., August 1, 2008; 23(8): 1917 - 1923. [Abstract] [Full Text] [PDF]

				A. Kuorelahti, S. Rulli, I. Huhtaniemi, and M. Poutanen Human Chorionic Gonadotropin (hCG) Up-Regulates wnt5b and wnt7b in the Mammary Gland, and hCG{beta} Transgenic Female Mice Present with Mammary Gland Tumors Exhibiting Characteristics of the Wnt/{beta}-Catenin Pathway Activation Endocrinology, August 1, 2007; 148(8): 3694 - 3703. [Abstract] [Full Text] [PDF]

				M. Udler, A.-T. Maia, A. Cebrian, C. Brown, D. Greenberg, M. Shah, C. Caldas, A. Dunning, D. Easton, B. Ponder, et al. Common Germline Genetic Variation in Antioxidant Defense Genes and Survival After Diagnosis of Breast Cancer J. Clin. Oncol., July 20, 2007; 25(21): 3015 - 3023. [Abstract] [Full Text] [PDF]