High Expression of LMTK3 is an Independent Factor Indicating a Poor Prognosis in Estrogen Receptor a-positive Breast Cancer Patients

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1 Original Articles Jpn J Clin Oncol 2014;44(10) doi: /jjco/hyu113 Advance Access Publication 27 August 2014 High Expression of LMTK3 is an Independent Factor Indicating a Poor Prognosis in Estrogen Receptor a-positive Breast Cancer Patients Tomoko Asano 1, Shinya Sato 2,3, Nobuyasu Yoshimoto 1, Yumi Endo 1, Yukari Hato 1, Yu Dong 1, Satoru Takahashi 2, Yoshitaka Fujii 1 and Tatsuya Toyama 1,* 1 Department of Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, 2 Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya and 3 Division of Diagnostic Pathology, Nagoya City East Medical Center, Nagoya, Japan *For reprints and all correspondence: Tatsuya Toyama, Department of Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya , Japan. toyamat-ncu@umin.ac.jp Received April 12, 2014; accepted July 22, 2014 Objective: Over 70% of breast cancers are estrogen receptor alpha-positive, and endocrine therapy targeting estrogen action decreases mortality from breast cancer. Recently, a novel protein kinase that regulates estrogen receptor alpha activity, lemur tyrosine kinase-3, has been identified. In this study, we investigated whether messenger RNA expression and polymorphisms of the gene encoding the kinase, LMTK3, are associated with prognosis in breast cancer patients during long-term follow-up. Methods: First, we investigated the relationship between messenger RNA expression of LMTK3 and patient outcome in 219 breast cancers. The effects of several variables on survival were tested by Cox proportional hazards regression analysis. Next, we performed LMTK3 genotyping in 471 breast cancers to clarify the prognostic role of these polymorphisms. Results: OurdatashowedthatLMTK3 expression level was not associated with prognosis in all patients. We then analyzed the impact of LMTK3 mrna expression on the prognosis of breast cancer according to estrogen receptor alpha status. Both disease-free survival and overall survival were significantly shorter in estrogen receptor alpha-positive patients with high LMTK3 expression receiving adjuvant endocrine therapy than in those patients with low LMTK3 expression. Multivariate Cox regression analysis revealed that high LMTK3 expression was an independent poor prognostic factor in estrogen receptor alpha-positive breast cancer patients. We did not find any correlation between LMTK3 genotypes and prognosis of breast cancer patients in our series. Conclusions: Our results show that high expression of LMTK3 is an independent prognostic factor in estrogen receptor alpha-positive breast cancer patients receiving adjuvant endocrine therapy. Key words: breast cancer LMTK3 polymorphism INTRODUCTION Estrogen receptor a (ERa) is a member of the nuclear receptor family and regulates the transformed phenotype of over 70% of breast cancers (1). Treatment options for such patients include endocrine therapies that inhibit ERa signaling, either by antagonizing ligand binding to ERa (selective ER # The Author Published by Oxford University Press. All rights reserved. For Permissions, please journals.permissions@oup.com

2 890 LMTK3 mrna expression in breast cancers modulators, e.g. tamoxifen), downregulating ERa (selective ER downregulators, e.g. fluvestrant) or suppressing estrogen production (aromatase inhibitors and gonadotropin-releasing hormone agonists) (2). However, some patients with breast cancer do not respond to any form of endocrine treatment (de novo resistance), and virtually all patients who initially respond eventually develop endocrine resistance (acquired resistance). ERa is not the only survival pathway driving ERa-positive breast cancer, and escape pathways when ERa is targeted are already functioning or begin to function during treatment. Using sirna screening, Giamas et al.(3) identified a novel protein kinase that regulates ERa activity, lemur tyrosine kinase-3 (LMTK3). They showed that LMTK3 regulates the stability and activity of ERa, and demonstrated that higher LMTK3 protein expression in breast cancers was associated with more aggressive phenotype and could predict endocrine resistance (4,5). Stebbing et al.(5) reported that inhibition of LMTK3 in tamoxifen-resistant breast cancer resulted in re-sensitization to tamoxifen, and suggested that LMTK3 was involved in endocrine resistance. They also showed that its germline polymorphisms rs (T.C) T/T genotype and rs (G.A) G/G or A/G genotypes were associated with favorable prognosis in breast cancer (4), although these polymorphisms were reported not to have any clinical impact on prognosis in gastric cancer (6). Multiple mechanisms responsible for endocrine resistance have been proposed. Mechanisms of endocrine resistance in ERa-positive breast cancers include loss of ERa expression, post-transcriptional modifications of ERa, increased activator protein 1 (AP1) activity and deregulation of ERa co-activators, increased receptor tyrosine kinase (RTK) signaling leading to the activation of the Erk and PI3K pathways, and deregulation of the cell cycle and apoptotic machinery (7,8). ESR1 mutations were recently reported to be involved in endocrine resistance in ERa-positive breast cancers (9,10). Here, we investigated whether messenger RNA (mrna) expression of LMTK3 and its polymorphisms are associated with prognosis in Japanese ERa-positive breast cancer patients during long-term follow-up. PATIENTS AND METHODS PATIENTS A total of 471 breast carcinomas from 1983 to 2005, from the archive of the Department of Breast and Endocrine Surgery, Nagoya City University Hospital in Japan, were available for polymorphism assay and of these, 219 breast carcinomas from 2001 to 2005 were available for mrna analysis. Tissues were fixed in 10% buffered formalin and embedded in paraffin, or snap-frozen in liquid nitrogen, immediately after resection and stored at 2808C until RNA extraction. Informed consent was obtained before surgery. The histological grade was estimated according to the Bloom and Richardson method proposed by Elston and Ellis (11). Disease-free survival (DFS) was defined as the interval from the date of primary surgery to the earliest occurrence of one of the following: locoregional recurrence, distant metastasis or death from any cause. Overall survival (OS) was defined as the interval from the date of primary surgery to death from any cause. The median followup period was 9.1 years (range months) for germline polymorphism analysis and 6.9 years (range months) for mrna expression analysis. This protocol was approved by the Institutional Review Board of Nagoya City University Graduate School of Medical Sciences and conformed to the guidelines of the 2004 Declaration of Helsinki. RNA EXTRACTION AND QUANTITATIVE REAL-TIME -PCR Total RNA was isolated using the RNeasy Mini Kit (Qiagen, Valencia, CA, USA) according to the manufacturer s protocol. Reverse transcription was performed using a High Capacity cdna Reverse Transcription Kit (Applied Biosystems, Foster City, CA, USA) according to the manufacturer s protocol. TaqMan Gene Expression assays (Applied Biosystems) were used to measure mrna expression of the LMTK3 gene and the housekeeping gene, ACTB. Quantitative real-time polymerase chain reaction (qpcr) assays were performed using a 7500 Fast Real-time PCR System (Applied Biosystems). The amplification reaction mixture comprised 2 ml of cdna (1 100 ng), 10 ml of TaqMan MasterMix (Applied Biosystems), 1 ml of TaqMan Gene Expression assay and 7 ml ofrnase-freewater in a total volume of 20 ml. The PCR conditions used were 508C for 2 min and 958C for 20 s, followed by 40 cycles of denaturation at 958C for 3 s, annealing and elongation at 608C for 30 s. Samples were amplified independently as duplicates. Results were converted into relative concentrations using an in-run standard curve, and the relative concentrations were normalized against the ACTB gene as an internal control. The cut-off of LMTK3 mrna was 0.4 in this study. IMMUNOHISTOCHEMISTRY OF ERa,PGR AND HER2 One 4 mm section from each paraffin block specimen was first stained with hematoxylin and eosin in order to ascertain that an adequate number of invasive ductal carcinoma cells were present and that the quality of fixation was adequate for immunohistochemical analysis. Serial sections (4 mm) were then prepared from suitable blocks and float-mounted on adhesivecoated glass slides for ERa, PgR and HER2 staining. The primary antibodies were mouse monoclonal anti-human antibodies against ERa (1D5; DAKO, Glostrup, Denmark) at a 1 : 100 dilution, and PgR (PgR636; DAKO) at a 1 : 100 dilution. Rabbit anti-human c-erbb2 oncoprotein antibody (DAKO) at a 1 : 200 dilution was used for HER2. The DAKO EnVision system (DAKO EnVision-labeled polymer, peroxidase) was used for detection of ERa, PgR and HER2. Immunostained specimens were scored after the entire slide had been evaluated by light microscopy. The expression of ERa was scored by assigning a proportion score and an intensity score according to Allred s procedure (1). Any brown nuclear staining in invasive

3 Jpn J Clin Oncol 2014;44(10) 891 breast epithelium was counted toward the proportion score. Tumors with scores of 3 or greater were considered to be positive for ERa expression. HER2 immunostaining was evaluated using the same method as employed by the HercepTest (DAKO). To determine the score of HER2 expression the membrane staining pattern was estimated and scored on a scale of 0to3þ. Tumors with scores of 0 and 1 were considered to be negative, and tumors with a score of 3 were considered to be positive for HER2 overexpression. All tumors with a score of 2 were omitted from the analysis in this study because fluorescent in situ hybridization analysis was not carried out. LMTK3 RS AND RS GENOTYPING Genomic DNA for genotyping was extracted from wholeblood samples using the Wizard SV Genomic DNA purification system (Promega, Madison, WI, USA) according to the manufacturer s instructions. TaqMan Pre-Designed SNP Genotyping assays for rs and rs were used. Genotyping was carried out using TaqMan PCR assays (Applied Biosystems) in 96-well arrays that included blank wells as negative controls according to the manufacturer s instructions. TaqMan PCR and genotyping analyses were carried out on the Applied Biosystems 9600 Emulation system. STATISTICAL ANALYSIS Survival curves were analyzed using the Kaplan Meier method and verified by log-rank test. DFS was defined as the interval from the date of primary surgery to the date of the first documented relapse and overall survival was defined as the interval from the date of primary surgery to death from any cause. DFS was censored at the date of last follow-up if patients were still relapse-free and alive, and OS was censored at the time when patients were alive. The relationships between LMTK3 mrna expression and clinicopathological factors were assessed by x 2 and Fisher s exact probability tests. A Cox proportional hazards regression analysis was used for univariate and multivariate analyses of prognostic values. The level of significance was set to P, Statistical calculations were performed with JMP10 software (SAS institute, Inc., Cary, NC, USA). RESULTS LMTK3 MRNA EXPRESSION AND PROGNOSIS OF BREAST CANCER PATIENTS First, we investigated the relationship between mrna expression of LMTK3 and patient outcome in 219 breast cancers. We analyzed the correlation between various expression levels of LMTK3 mrna and prognosis of breast cancer patients in this series. Our results showed that the best correlation of relative LMTK3 mrna expression with patients prognosis was 0.4. Therefore, we chose 0.4 as the cut-off to use for LMTK3 mrna in this study. We did not find any association between LMTK3 mrna expression level and clinicopathological features in our series (Table 1). Our data showed that LMTK3 mrna expression level was not associated with prognosis in all patients analyzed in this series (Fig. 1A and B). As LMTK3 is considered to be involved in Table 1. Association between LMTK3 messenger ribonucleic acid (mrna) expression and clinicopathological characteristics All patients, Low LMTK3, Patients Age (years) High LMTK3, P value,50 91 (42) 77 (44) 14 (33) (58) 99 (56) 29 (67) Tumor size 2 cm 66 (30) 52 (30) 14 (33) cm 149 (68) 121 (68) 28 (65) Unknown 4 (2) 3 (2) 1 (2) Nodal status Negative 115 (53) 97 (55) 18 (42) Positive 88 (40) 70 (40) 18 (42) Unknown 16 (7) 9 (7) 7 (16) Grade 1 71 (32) 51 (29) 20 (47) (37) 69 (39) 12 (28) 3 67 (31) 56 (32) 11 (25) Histology IDC 188 (86) 151 (86) 37 (86) ILC 10 (5) 8 (5) 2 (5) Others 21 (9) 17 (9) 4 (9) ERa status Positive 154 (70) 120 (68) 34 (79) Negative 65 (30) 56 (32) 9 (21) PgR status Positive 138 (63) 109 (62) 29 (67) Negative 81 (37) 67 (38) 14 (33) HER2 status Positive 25 (11) 22 (13) 3 (7) Negative 194 (89) 154 (87) 40 (93) Adjuvant therapy Endocrine therapy 104 (47) 84 (48) 20 (47) Chemotherapy 52 (24) 45 (26) 7 (16) Endocrine þ chemotherapy 50 (23) 36 (20) 14 (33) None 13 (6) 11 (6) 2 (4) LMTK3, lemur tyrosine kinase-3; ERa, estrogen receptor a; PgR, progesterone receptor; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma.

4 892 LMTK3 mrna expression in breast cancers endocrine resistance, we then analyzed the impact of LMTK3 mrna expression on the prognosis of breast cancer according to ERa status. Both DFS and OS were significantly shorter in ERa-positive breast cancer patients with high LMTK3 mrna expression than in those patients with low LMTK3 mrna expression (Fig. 1C and D, P ¼ and P ¼ 0.002, Figure 1. Patient outcomes according to lemur tyrosine kinase-3 (LMTK3) mrna expression levels. Kaplan Meier survival curves are shown according to LMTK3 mrna expression levels. Graphs show DFS and OS, respectively, for all breast cancer patients (A, B), estrogen receptor alpha (ERa)-positive breast cancer patients (C, D) and ERa-positive breast cancer patients receiving adjuvant endocrine therapy (E, F). No correlation was found between LMTK3 mrna expression and survival in ERa-negative breast cancer patients (G, H).

5 Jpn J Clin Oncol 2014;44(10) 893 respectively). We also analyzed the impact of LMTK3 mrna expression on the prognosis of ERa-positive breast cancer patients receiving adjuvant endocrine therapy. We found no association between LMTK3 mrna expression level and clinicopathological features in ERa-positive breast cancer patients receiving adjuvant endocrine therapy (Table 2). High LMTK3 mrna expression was significantly associated with shorter DFS and OS in those patients, as shown in Fig. 1Eand F(P ¼ and P ¼ , respectively). Univariate and multivariate Cox regression analysis of factors associated withdfsoroswasperformedinera-positive breast cancer patients receiving adjuvant endocrine therapy. Our data revealed that high LMTK3 mrna expression was an independent factor indicating poor prognosis in ERa-positive breast cancer patients receiving adjuvant endocrine therapy (P ¼ 0.035, hazard ratio of death ¼ 4.16, 95% confidence interval ¼ ) (Table 3). On the other hand, LMTK3 mrna expression levels were neither associated with DFS nor OS in ER-negative breast cancer patients (Fig. 1G and F). LMTK3 RS AND RS GENOTYPING A total of 471 breast cancer tissues were subjected to LMTK3 rs (T.C) and rs (G.A) genotyping. The final success rates of LMTK3 genotyping in this cohort were 462 (98%) for rs and 461 (98%) for rs There were no significant associations between the genotypes of these polymorphisms and clinical characteristics (Table 4). We also investigated the relationship between LMTK3 genotypes and patient outcomes. However, we did not find any correlation between the genotypes of these polymorphisms and the prognosis of all breast cancer patients in this study (Fig. 2A andb).inera-positive patients, there was also no correlation between LMTK genotypes and patient outcomes (Fig. 2C and D). DISCUSSION Our data show that high expression of LMTK3 is an independent factor predictive of a poor prognosis in ERa-positive breast cancer patients, but that LMTK3 mrna expression levels are not associated with patient outcomes in ERanegative breast cancers. Our data also show that LMTK3 polymorphisms are not associated with prognosis in Japanese breast cancer patients. LMTK3 was previously reported to be a regulator of ERa function, regulating the stability and activity of ERa at the mrna level, interacting with FOXO3a and leading to enhanced ERa transcriptional activity via increased binding of FOXO3a to the ERa promoter, and at the protein level phosphorylating ERa, which results in its protection from proteosomal degradation (3). Giamas et al.(3) reported that high LMTK3 protein expression was associated with poor prognosis in European breast cancer patients. Stebbing et al. also Table 2. Association between LMTK3 mrna expression and clinicopathological characteristics in ERa-positive breast cancer patients receiving endocrine therapy All patients, Low LMTK3, High LMTK3, P value Patients Age (years),50 64 (44) 53 (47) 11 (33) (56) 60 (53) 22 (67) Tumor size 2 cm 49 (34) 38 (34) 11 (33) cm 97 (66) 75 (66) 22 (67) Nodal status Negative 70 (48) 59 (52) 11 (33) Positive 66 (45) 51 (45) 15 (45) Unknown 10 (47) 3 (3) 7 (22) Grade 1 56 (38) 41 (36) 15 (45) (43) 52 (46) 10 (30) 3 28 (19) 20 (18) 8 (25) Histology IDC 126 (86) 98 (87) 28 (85) ILC 10 (7) 8 (7) 2 (6) Others 10 (7) 7 (6) 3 (9) PgR status Positive 124 (85) 97 (86) 27 (82) Negative 22 (15) 16 (14) 6 (18) HER2 status Positive 10 (7) 7 (6) 3 (9) Negative 136 (93) 106 (94) 30 (91) Adjuvant therapy Endocrine therapy 100 (68) 80 (71) 20 (61) Endocrine þ chemotherapy 46 (32) 33 (29) 13 (39) reported that high LMTK3 protein expression was associated with poor prognosis in a cohort of Singapore breast cancer patients. We show that ERa-positive patients receiving adjuvant endocrine therapy and exhibiting higher LMTK3 mrna expression demonstrated not only shorter DFS but also OS compared with those with lower LMTK3 mrna expression. Therefore, our data support the findings of these previous reports. Notably, LMTK3 mrna expression was not associated with survival in ERa-negative breast cancers in this study. Stebbing et al. (5) recently reported that LMTK3 was able to modulate the expression of heat-shock 22 kda protein 8 (HSPB8), which is a member of the small heat-shock protein superfamily. Gonzalez-Malerva et al. (12) reported that

6 894 LMTK3 mrna expression in breast cancers Table 3. Univariate and multivariate Cox regression analysis of factors associated with prognosis in ERa-positive breast cancer patients receiving endocrine therapy Variables Univariate (DFS) Univariate (OS) Multivariate (DFS) Multivariate (OS) P value P value P value HR (95% CI) P value HR (95% CI) Age (years),50 64 (44) 1 (Reference) 1 (Reference) (56) ( ) ( ) Tumor size 2 cm 49 (34) 1 (Reference) 1 (Reference).2 cm 97 (66) ( ) ( ) Nodal status Negative 70 (48) 1 (Reference) 1 (Reference) Positive 66 (45) ( ) ( ) Grade 1,2 118 (81) 1 (Reference) 1 (Reference) 3 28 (19) ( ) ( ) PgR Positive 124 (85) 1 (Reference) 1 (Reference) Negative 22 (15) ( ) ( ) HER2 Positive 10 (7) 1 (Reference) 1 (Reference) Negative 136 (93) ( ) ( ) Chemotherapy With 46 (32) 1 (Reference) 1 (Reference) Without 100 (68) ( ) ( ) LMTK3 mrna expression Low 113 (77) 1 (Reference) 1 (Reference) High 33 (23) ( ) ( ) DFS, disease-free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval. HSPB8 protected breast cancer cells from tamoxifen and blocked autophagy, and that silencing HSPB8 induced autophagy and caused cell death. They suggested that HSPB8 expression was involved in tamoxifen resistance in breast cancer cells (12). The LMTH3-HSPB8 pathway could, therefore, be one of the possible mechanisms underlying the endocrineresistance of ERa-positive breast cancers. Although Stebbing et al. (4) reported that nuclear or cytoplasmic LMTK3 expression was associated with high tumor grade, there was no association between LMTK3 mrna expression and tumor grade in our series. They also reported that tumors with high nuclear or cytoplasmic LMTK3 protein expression were more likely to be ERa and PgR-negative (4). However, we did not find any correlation between LMTK3 mrna expression and ERa or PgR expression in our series. These discrepancies might be due to differences in the expression of mrna and protein, or due to the smaller sample size in our study. Multiple mechanisms responsible for endocrine resistance have been proposed so far. Although the loss of ERa expression has been implicated as a potential mechanism of acquired resistance, loss of ERa expression occurs in only a minority of resistant breast cancer cases (13). Despite the sustained presence of the receptor, these tumors can eventually develop resistance to endocrine therapy. Mutations affecting ERa have been proposed as another possible mechanism for this resistance. Recently, activating ESR1 mutations have been found to be relatively frequent in advanced ERa-positive endocrineresistant breast cancers (9,10) although ESR1 mutations are infrequent in primary breast cancer tissues (14). Robinson et al. and Toy et al.(9,10) showed that mutations in ESR1 affecting the ligand-binding domain resulted in ERa that were highly

7 Jpn J Clin Oncol 2014;44(10) 895 Table 4. Association between genotypes of LMTK3 germline polymorphisms and clinicopathological characteristics rs rs CC or CT, 393 TT, 69 GG or AG, 449 AA, 12 P value Age (years), (35) 29 (42) 155 (35) 8 (67) (65) 40 (58) 294 (65) 4 (33) Tumor size 2 cm 126 (32) 26 (38) 143 (32) 6 (50) cm 251 (64) 40 (58) 287 (64) 6 (50) Unknown 16 (4) 3 (4) 19 (4) 0 (0) Node status Negative 212 (54) 36 (52) 236 (53) 4 (33) Positive 162 (41) 29 (42) 190 (42) 8 (67) Unknown 19 (5) 4 (6) 23 (5) 0 (0) Grade 1,2 301 (77) 57 (83) 345 (77) 10 (83) (23) 12 (17) 104 (23) 2 (17) Histology IDC 357 (91) 63 (91) 406 (90) 12 (100) ILC 8 (2) 4 (6) 13 (3) 0 (0) Others 28 (7) 2 (3) 30 (7) 0 (0) ER status Positive 260 (66) 54 (78) 312 (69) 10 (83) Negative 133 (34) 15 (22) 137 (31) 2 (17) PgR status Positive 251 (64) 49 (71) 298 (66) 8 (67) Negative 142 (36) 20 (29) 151 (34) 4 (33) HER2 status Positive 60 (15) 7 (10) 60 (13) 2 (17) Negative 333 (85) 62 (90) 389 (87) 10 (38) active in the absence of estrogen and could cause resistance to therapy with aromatase inhibitors. One possible mechanism for endocrine resistance is the crosstalk between ERa and RTK signaling. The classic function of ERa is its action as a transcriptional factor in the nucleus, where it alters the expression of genes important for tumor growth and survival. The ERa signaling pathway is also regulated by membrane RTK, including epidermal growth factor receptor, HER2 and insulin-like growth factor receptor (8). A small subset of the cellular pool of ERa localized outside the nucleus and/or at the cell membrane associates in response to estrogen with growth factors and RTKs and with coactivator molecules such as Srk kinase. Increased expression or signaling of these growth factor receptor pathways has been associated with endocrine therapy resistance (8,15). Recently, Carroll and colleagues showed that ERa binding to DNA is dynamically regulated, and that different ERa-binding profiles are associated with different clinical outcomes (16 18). They propose that the transcription factor FOXA1, one of the Forkhead proteins, could mediate the reprogramming of ERa activity by facilitating the recruitment of ERa to different locations on DNA, leading to the development of resistance to endocrine therapy (16,18). Cyclin D1 is one of the cell cycle regulators, promoting progression through the G1 S phase, following complex formation with CDK4/6 and phosphorylation of the retinoblastoma protein. Cyclin D1 gene amplification was reported to be involved in resistance to endocrine therapy (19,20). Giamas et al.(3) reported that the LMTK3 polymorphisms, rs (T.C) T/T genotype and rs (G.A) G/G or A/G genotype were associated with breast cancer outcome

8 896 LMTK3 mrna expression in breast cancers Figure 2. Patient outcomes according to the genotypes of LMTK3 germline polymorphisms. Kaplan Meier survival curves are shown according to the genotypes of LMTK3 polymorphisms for DFS for all breast cancer patients (A, B), and for ERa-positive breast cancer patients (C, D). in European breast cancer patients. Based on this, we examined the correlation between genotypes of these polymorphisms and breast cancer outcome in Japanese patients. However, we found no correlation between them in our series. This discrepancy might be due to ethnic differences because the allelic distribution differs between Japanese and Caucasian populations (6). Wakatsuki et al. (6) previously reported that no correlation was found between genotypes of these polymorphisms and prognosis in Japanese and US gastric cancer patients although some correlations were found in subgroup analyses in their series. In this study, we show that high expression of LMTK3 is a poor prognostic factor in ERa-positive breast cancer patients receiving adjuvant endocrine therapy, and that LMTK3 mrna expression is not associated with survival in ERa-negative breast cancer patients. Funding This work was supported by a grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, MEXT/JSPS KAKENHI grant number Conflict of interest statement None declared. References 1. Harvey JM, Clark GM, Osborne CK, Allred DC. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. JClin Oncol 1999;17: Early Breast Cancer Trialists Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365: Giamas G, Filipovic A, Jacob J, et al. Kinome screening for regulators of the estrogen receptor identifies LMTK3 as a new therapeutic target in breast cancer. Nat Med 2011;17: Stebbing J, Filipovic A, Ellis IO, et al. LMTK3 expression in breast cancer: association with tumor phenotype and clinical outcome. Breast Cancer Res Treat 2012;132: Stebbing J, Filipovic A, Lit LC, et al. LMTK3 is implicated in endocrine resistance via multiple signaling pathways. Oncogene 2013;32: Wakatsuki T, LaBonte MJ, Bohanes PO, et al. Prognostic role of lemur tyrosine kinase-3 germline polymorphisms in adjuvant gastric cancer in Japan and the United States. Mol Cancer Ther 2013;12: Musgrove EA, Sutherland RL. Biological determinants of endocrine resistance in breast cancer. Nat Rev Cancer 2009;9: Osborne CK, Schiff R. Mechanisms of endocrine resistance in breast cancer. Annu Rev Med 2011;62: Toy W, Shen Y, Won H, et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet 2013;45: Robinson DR, Wu YM, Vats P, et al. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet 2013;45: Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 1991;19: Gonzalez-Malerva L, Park J, Zou L, et al. High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci USA 2011;108:

9 Jpn J Clin Oncol 2014;44(10) Gutierrez MC, Detre S, Johnston S, et al. Molecular changes in tamoxifen-resistant breast cancer: relationship between estrogen receptor, HER-2, and p38 mitogen-activated protein kinase. J Clin Oncol 2005;23: Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 2012;490: Massarweh S, Osborne CK, Creighton CJ, et al. Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function. Cancer Res 2008;68: Ross-Innes CS, Stark R, Teschendorff AE, et al. Differential oestrogen receptor binding is associated with clinical outcome in breast cancer. Nature 2012;481: Lupien M, Meyer CA, Bailey ST, et al. Growth factor stimulation induces a distinct ER(alpha) cistrome underlying breast cancer endocrine resistance. Genes Dev 2010;24: Hurtado A, Holmes KA, Ross-Innes CS, Schmidt D, Carroll JS. FOXA1 is a key determinant of estrogen receptor function and endocrine response. Nat Genet 2011;43: Lundgren K, Brown M, Pineda S, et al. Effects of cyclin D1 gene amplification and protein expression on time to recurrence in postmenopausal breast cancer patients treated with anastrozole or tamoxifen: a TransATAC study. Breast Cancer Res 2012;14:R Jirstrom K, Stendahl M, Ryden L, et al. Adverse effect of adjuvant tamoxifen in premenopausal breast cancer with cyclin D1 gene amplification. Cancer Res 2005;65:

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