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Luteinizing Hormone Signaling and Breast Cancer: Polymorphisms and Age of Onset

Department of Surgery (B.L.P., B.J.I.), University of Western Australia, Nedlands 6907, Australia; and Departments of Medical Oncology (B.L.P., D.P., M.E.K., I.L.v.S., E.M.J.J.B.) and Internal Medicine (A.P.N.T.), Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: Els M. J. J. Berns, Ph.D., Department of Medical Oncology, Josephine Nefkens Institute, Room Be 424, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. E-mail: berns{at}bidh.azr.nl.

	Abstract

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Estrogen exposure has repeatedly been shown to associate with the risk of developing breast cancer. Estrogen synthesis is under the control of LH and FSH, where LH, through its receptor (LHR), stimulates production of ovarian androgens; and FSH, their aromatization to estrogens. Here, we investigated whether functional polymorphic variants in the LH signaling pathway are associated with the risk of breast cancer or its clinical phenotype.

A PCR-restriction fragment length polymorphism genotyping approach was used to investigate this in 266 breast cancers. The LHR18insLQ allele does not seem to influence breast cancer risk. However, women who were homozygous for the LHR18insLQ allele were, on average, 8.3 yr younger at diagnosis, compared with those homozygous for the wild-type LHR allele (mean age, 51.9 yr vs. 60.2 yr; P = 0.03). Trends were observed for associations between LHR18insLQ carriers and nodal involvement or larger tumor size. Patients who were LHR18insLQ carriers revealed a significantly worse overall survival, compared with those who were homozygous for LHR [hazard ratio = 2.4; 95% CI (1.3–4.3); P = 0.006]. In contrast, no associations between the LH genotype and any of the clinical parameters were observed. Our findings suggest that the LHR18insLQ gene polymorphism determines an earlier age of disease onset and is prognostic for poor outcome of breast cancer.

	Introduction

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BREAST CANCER IS the most common form of cancer among women in industrialized countries and is the leading cause of death between the ages of 40 and 55 yr (1). In addition to age and family history of the disease, exposure to endogenous and exogenous estrogens is a well-known risk factor. Elevated serum estrogen levels and increased urinary excretion rates of E1, E2, and E3 have been found in breast cancer cases, compared with controls. Because exposure to estrogens is known to influence breast cancer risk, genetic variants within the hormone metabolic pathway, including enzymes involved in the biosynthesis and metabolism of estradiol (i.e. CYP17, CYP19, CYP2D6, CYP1A1, COMT), are currently being considered as candidate low-risk factors for breast cancer. The data from most of these studies, however, is still inconclusive (reviewed in Refs. 2 and 3). In addition to increasing the risk of cancer, polymorphisms in genes involved in hormone synthesis and metabolism are also associated with various clinicopathological features of tumors and with patient prognosis. For example, variants of the human steroid 5- reductase type II gene are associated with an earlier age of disease onset, poor tumor grade, and breast cancer patient (disease-free) survival (4), whereas variants of the CYP19 and CYP1B1 genes have been associated with positive estrogen receptor and progesterone receptor tumor status (3).

Estrogen production in the ovary is under the control of the pituitary hormones FSH and LH (reviewed in Ref. 5). FSH regulates aromatase (CYP19) activity, whereas LH is responsible for the actual production of androgens in the ovarian theca cells, thus providing the substrate for aromatization to estrogens in the granulosa cells. LH and its placental homolog human chorionic gonadotropin (hCG) act through the LH receptor (LHR), a member of the heptahelical, G-protein-coupled receptor family. LHR is expressed in the gonads as well as various other tissues, including normal breast tissue, primary breast tumors, and breast cancer cell lines. Inactivating mutations in LHR are associated with strong phenotypic effects, such as 46,XY pseudohermaphroditism and primary amenorrhea and anovulation in women. However, linkage of polymorphic variants of LHR to disease phenotypes has not been reported. Because LH and the LHR are both involved in estradiol synthesis, functionally important polymorphisms in these genes could alter the level of estrogen exposure and thereby contribute to breast cancer risk determination.

A genetic variant of LHß has recently been described that is characterized by a single-nucleotide polymorphism (SNP), resulting in amino acid change Trp to Arg at codon 8 (LH8R allele). This polymorphism is linked to another SNP, resulting in amino acid change Ile to Thr at codon 15, introducing an extra glycosylation site at codon 13 (6). Compared with wild-type LH (LH8W allele) this variant has higher in vitro bioactivity and is associated with higher levels of circulating estradiol and testosterone but has a shorter circulatory half-life (7). The variant LH is thought to be functionally weaker than the wild-type form.

Seven polymorphisms have been described in the LHR gene (reviewed in Ref. 8). Six are located in the extracellular ligand-binding domain, and 3 of these may have functional relevance. They include 2 SNPs, resulting in amino acid changes Asn to Ser at codon 291 and Ser to Asn at codon 312 in exon 10, both of which are potential N-linked glycosylation sites that may be involved in hormone binding. The remaining polymorphism is a palindromic insertion of 6 bp (CTGCAG, Leu-Gln at codon 18) in exon 1, position 55–60, near the N terminus of the mature protein (LHR18insLQ; Refs. 9 and 10). It is located immediately upstream of the proposed signal peptide cleavage site and may therefore interfere with LHR protein synthesis, posttranslational modification, and targeting to the plasma membrane. Interference with the LHR protein at this location has a high probability of changing receptor function, because an insertion of 33 amino acids at the same position causes complete female phenotype in a 46,XY patient (11).

Interestingly, the frequency of LH8R allele seems to be generally higher in populations from Northern Europe, compared with Asian populations (6, 12). In contrast, the LHR18insLQ allele has been reported to be virtually absent from the Japanese population (10). Because the incidence of breast cancer in Northern Europe is 2-fold higher than in Asian or Japanese populations (13), we hypothesized that LH8R or LHR18insLQ could be related to breast cancer occurrence, clinicopathological features, and patients prognosis.

The aim of the present study was to assess whether polymorphisms in the LH and LHR genes are possible susceptibility alleles and determinants of clinical phenotype in a cohort of breast cancer patients of Caucasian descent.

	Subjects and Methods

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Subjects and sample preparation

Eligible cases were women with primary breast cancer (n = 266) who were treated by mastectomy or breast-conserving surgery between 1990 and 1993 at two main hospitals, the Sir Charles Gairdner and the Royal Perth Hospital, in Perth, Western Australia. Genomic DNA was extracted from surgically resected frozen tumor samples, using standard procedures. The LH and LHR genes are located on chromosomal arms 19q and 2p, respectively, regions that are infrequently lost in breast cancer. However, because the primary breast tumor specimens from which the DNA was obtained for genotyping always contain a relative high proportion (>50%) of nontumor tissue (stroma, lymphoid, nontumor areas), this contribution of germ line DNA ensures accurate genotyping of the LH and LHR genes.

The median age at surgery was 58 yr (range, 18–92 yr), and the median follow-up time was 87 months (range, 2–116 months). Additional patient and tumor characteristics for this consecutive breast cancer series were described by Soong et al. (14) and are summarized in Table 1. Information on family history of breast cancer was not available. The majority of subjects (>95%) were Caucasian of North-Western European descent. Ethics approval was obtained from the local ethics committee. To test for control frequencies, a comparable local healthy population was chosen. This control series comprised DNA samples from peripheral blood samples obtained from 110 healthy women from the same population that were age-matched to the breast cancer patients.

High molecular weight genomic DNA was used as template for PCR amplification of exon 2, intron 2, and exon 3 of LH-ß, essentially as described by Furui et al. (15). For the RFLP-assay, the restriction enzymes Nco1 and Fok1 (Amersham Pharmacia Biotech, Little Chalfont, Buckinghamshire, UK) were used to detect the linked polymorphisms at codons 8 and 15 in LHß, respectively, as described (15). Suspected LH variants were confirmed by sequence analysis using the Cycle Reader DNA Sequencing kit (Fermentas, St. Leon-Rot, Germany) and 5'-³³P end-labeled primers. The terminated PCR products were separated on a 6% denaturing polyacrylamide gel containing 8 M urea. Gels were dried and exposed overnight with Biomax MR films (Eastman Kodak Co., Rochester, NY). The presence of the LH variant was confirmed by comparison with the published wild-type sequence (Hs.: 154704; MIM: 152780).

PCR-RFLP assay for LHR genotype analysis

High molecular weight genomic DNA was used as template for PCR amplification of exons 1 and 10 of LHR (Hs.: 1796; MIM: 152790), as described by Atger et al. (9). The RFLP-assay was performed as described by Rodien et al. (10). To detect the 6-bp insertion at position 55 in exon 1 of LHR (LHR18insLQ allele), the restriction enzyme PvuII (Amersham Pharmacia Biotech) was used. To confirm the results, PCR-RFLP analysis was repeated on samples that tested heterozygote or homozygote for LHR18insLQ, as well as 10% of LHR wild-type samples.

Statistical analysis

Pearson’s ² test was used to test for independence of the alleles (Hardy-Weinberg equilibrium). The ² test was used to determine associations between the various patient and tumor characteristics and the LH or LHR genetic variants. Information on patient survival was obtained from the Western Australian Health Department death registry. At the end of the study, 45 patients (17%) had died of their disease. Uni- and multivariate survival analysis was carried out using Cox regression analysis. All tests were two tailed, and statistical significance was assumed at P 0.05. Statistical analyses were carried out using the SPSS software package (SPSS, Inc., Chicago, IL).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Variant-LH and insLQ-LHR genotype frequencies

PCR-RFLP was used for the detection of polymorphisms in LH and its receptor, LHR, in a total of 266 breast cancer cases and 108 control samples. Samples were classified as "carrier" if they were confirmed as being either heterozygote or homozygote for the polymorphism. The combined homo- and heterozygote frequency of the LH8R allele in this breast cancer series was 16.5% (Table 1). The observed LH8R carrier frequency is similar to that for healthy control subjects from Western and Southern European Caucasian populations, i.e. 14–15% reported in 569 subjects. The combined homo- and heterozygote frequency of the LHR18insLQ allele was 44.4% (Table 1). This LHR18insLQ carrier frequency is not significantly different from that of the control group of 108 healthy women from the same hospital (54.6%), or from the 44.1% as reported for 102 subjects (6, 10, 12). The genotype distribution for both the LH and LHR genes was in Hardy-Weinberg equilibrium (P = 0.26 and P = 0.66, respectively). The LHR Asn291Ser (AATAGT) allele frequency was examined but was too low (6%) to be informative and therefore was not further analyzed (results not shown). No association between the carriers was apparent: 44% of patients who were wild-type for LH had the LHR18insLQ allele, compared with 48% for patients with the LH8R allele (P = 0.62).

Variant-LH and insLQ-LHR genotype and clinicopathological features

Associations between LH8R, LHR18insLQ and clinicopathological features of breast cancer are shown in Table 1. The LHR18insLQ variant does not seem to predispose to breast cancer but does seem to influence the phenotype of the tumor that develops. There was a significant correlation between median age at diagnosis of breast cancer and LHR genotype (P = 0.05). Trends were observed for associations between LHR18insLQ and nodal involvement (P = 0.13) and larger tumor size (P = 0.06). In contrast, no evidence was found for associations between LH8R genotype and any of the established clinical or pathological parameters. Moreover, no difference in overall survival was seen between LH8R and wild-type LH breast cancer patients [HR = 0.7; 95% CI (0.3–1.8); P = 0.49].

We analyzed, in further detail, the relationship between LHR18insLQ genotype and the mean age of diagnosis in affected patients (Table 2). Breast cancer cases who were homozygous for LHR18insLQ were significantly younger than those who were homozygous for wild-type LHR (mean, 51.9 yr vs. 60.2 yr; P = 0.03; Fig. 1), with a calculated 3.5-yr-earlier age of diagnosis per allele copy. Cox regression univariate analysis revealed significantly worse overall survival for patients who were carriers of the LHR18insLQ allele, compared with those who were homozygous for wild-type LHR [HR = 2.4; 95% CI (1.3–4.3); P = 0.006]. Significantly worse overall survival was also seen when patients who were homozygous for wild-type LHR were compared with those who were homozygous for the LHR18insLQ allele [hazard ratio (HR) = 3.2; 95% CI (1.2–8.1); P = 0.02] or with patients heterozygous for LHR18insLQ allele [HR = 2.2; 95% CI (1.2–4.2); P = 0.01: Fig. 2]. The LHR18insLQ allele was not an independent factor for survival in multivariate analysis (results not shown).

View larger version (15K): [in this window] [in a new window]   Figure 1. LHR genotype and mean age at diagnosis of breast cancer.

View larger version (10K): [in this window] [in a new window]   Figure 2. Kaplan-Meier survival analysis, comparing the overall survival of patients homozygous for wild-type LHR (n = 148) with those heterozygous (n = 99) and homozygous (n = 19) for the variant, LHR18insLQ. Curves were compared using Cox regression analysis.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

The frequencies of LH8R and LHR18insLQ alleles were determined in a series of breast cancer cases that were previously characterized for clinicopathological features and for patient outcome (14). The present data suggest that the breast cancer patients investigated in this series do not have increased LH8R or LHR18insLQ allele frequencies, when compared with a healthy control population from the same area or with other healthy control groups as reported in the literature. Moreover, the genotype distribution for both the LH and LHR genes was in Hardy-Weinberg equilibrium. Based on these data, it seems unlikely that the detected polymorphisms reflect somatic changes in the DNA, which was obtained from breast tumor tissues. Furthermore, our results confirm two previous studies for variant LH that also found no difference in the frequency of LH8R between breast cancer cases and controls (19, 20). These studies also suggested that the LH8R is not associated with an increased risk of breast cancer. Although LH and the LHR are involved in estradiol synthesis, there is no relation to the ER status of the breast tumors. Furthermore, there were no significant associations between the LH8R allele and clinicopathological features of breast cancer, nor were there differences in overall survival between women who carried the wild-type LH allele or the LH8R allele. Information on recurrence-free survival was incomplete and therefore not included in the analysis (as described by us earlier, Ref. 14). Interestingly, the LHR18insLQ allele showed a significant association with age of diagnosis and a worse overall survival of breast cancer patients.

Even though the breast is not typically considered an LH-responsive tissue, receptors for LH/hCG have been found in human breast tumors and breast cancer cell lines. hCG can inhibit proliferation of some breast cancer cell lines in vitro (21). Furthermore, the protective effect of pregnancy on breast cancer has been proposed to be caused by binding of hCG to the LH/hCG receptor on breast epithelial cells, thereby causing differentiation, which, in turn, renders the cells less susceptible to neoplastic transformation (Ref. 21 ; reviewed in Ref. 13). Finally, Tanaki et al. (22) have proposed a gonadotropin-stimulated, intratumoral estrogen synthesis in which elevated gonadotropin levels, during the peri- and postmenopausal period, stimulate breast tissue to synthesize estrogens. Because this involves both LH and LH/hCG receptor, it is conceivable that polymorphisms in these genes also influence the level of local estrogen synthesis.

Although these data are intriguing, studies on ovariectomy in mouse models have shown that the effect of LH on regression of the mammary gland is indirect, through stimulation of estrogen production by the ovary. This is supported by a recent finding on transgenic mice that overexpress LH. Milliken et al. (22) showed that persistent overexpression of LH from the pituitary of transgenic, LHbetaCTP mice leads to precocious mammary gland development and ovary-dependent mammary hyperplasia. These mice develop spontaneous mammary tumors, compared with nontransgenic controls, where the ovary was the obligatory intermediate of LH action. In contrast, complete absence of LH signaling has a more subtle effect, as shown in one patient: a normal female phenotype with infertility caused by anovulation. In addition, signs of severe hypoestrogenization are present: small uterus, hyposecretory vagina, decreased bone mass, again illustrating the clear link between LH signal transduction and estrogen exposure (24).

Although the functional implications of the LQ insertion for LHR activity are still not clear, a possible role in breast carcinogenesis might be explained by differences in estrogen exposure or by an altered LH responsiveness. Whether the variant form of the receptor alters estrogen production by the ovary, and in this way indirectly affects breast carcinogenesis, needs further study.

In conclusion, our data suggest that neither the LH8R nor LHR18insLQ genotypes are associated with an increased risk of breast cancer. The LHR18insLQ allele is, however, implicated in an earlier age of diagnosis of this disease and with a more aggressive phenotype. To shed further light on these associations, the role of the LHR18insLQ allele in (early-onset) breast cancer needs to be investigated further, preferably in high-power longitudinal studies recording the incidence as well as prevalence in large populations with documentation of estrogen serum levels.

	Acknowledgments

 
We thank Anke van Kerkwijk for expert technical assistance and Drs. A. G. Uitterlinden and J. W. M. Martens for constructive discussion, advice, and reading of the manuscript.

	Footnotes

 
This work was supported by grants from the Postgraduate Research Travel Award (Convocation, the University of Western Australia Graduates Association) and the John Nott Cancer Fellowship and Research Award (Cancer Foundation of Western Australia) (to B.L.P.).

B.L.P. and D.P. contributed equally to the manuscript.

Abbreviations: hCG, Human chorionic gonadotropin; HR, hazard ratio; LHR, LH receptor; RFLP, restriction fragment length polymorphism; SNP, single-nucleotide polymorphism.

Received October 10, 2002.

Accepted December 20, 2002.

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This Article Abstract Full Text (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 Powell, B. L. Articles by Berns, E. M. J. J. Search for Related Content PubMed PubMed Citation Articles by Powell, B. L. Articles by Berns, E. M. J. J.