ATBF1-A Messenger RNA Expression Is Correlated with Better Prognosis in Breast Cancer

Vol. 11, 193–198, January 1, 2005 Clinical Cancer Research 193

Zhenhuan Zhang,1 Hiroko Yamashita,1 those expressing low levels. Univariate and multivariate Tatsuya Toyama,1 Hiroshi Sugiura,1 prognostic analyses showed that ATBF1-A mRNA expression is an independent prognostic factor for disease-free survival. Yoshiaki Ando,1 Keiko Mita,1 Maho Hamaguchi,1 3 2 Conclusions: In breast cancer, levels of ATBF1-A Makoto Kawaguchi, Yutaka Miura, and mRNA may serve as a predictive indicator of lymph node 1 Hirotaka Iwase metastasis. The results of this study also imply that ATBF1-A Departments of 1Breast and Endocrine Surgery and 2Bioregulation gene expression may have potential both as a marker of Research, Nagoya City University Medical School, Nagoya, Japan and endocrine responsiveness and also as a prognostic indicator 3Department of Pathology, Niigata Rosai Hospital, Japan Labor Health and Welfare Organization, Niigata, Japan for breast cancer progression.

ABSTRACT INTRODUCTION Purpose: The AT motif-binding factor 1 (ATBF1) gene Tissue-specific expression of the human a-fetoprotein was first identified as a suppressor of the A-fetoprotein (AFP) (AFP) gene is strongly stimulated by an enhancer element gene through its binding to an AT-rich enhancer element of located 3.3 to 4.9 kb upstream of the transcription initiation site this gene. The gene is located at chromosome 16q22.3-q23.1 (1, 2). One of the enhancer elements contains an AT-rich core where loss of heterozygosity has been observed in various sequence (called the AT motif; ref. 3). To determine the nuclear malignant tumors, especially in breast cancer. It was also factor in hepatoma cell lines that interacts with the human AFP found that in highly malignant AFP-producing gastric cancer enhancer AT motif, Morinaga et al. (4) screened a hepatoma cells the expression of AFP is inhibited by ATBF1-A. This led cDNA expression library with an AFP enhancer fragment that us to hypothesize that there was a link between levels of bore the AT motif. They succeeded in isolating a cDNA that ATBF1 expression and the metastatic potential of breast coded for an AT motif-binding factor, termed ATBF1. This was cancer and also, therefore, the prognosis of these patients. the largest DNA-binding protein identified to that time and the Experimental Design: In the present study, the level of first protein shown to contain multiple homeodomains and ATBF1-A mRNA expression was analyzed using quantitative multiple zinc finger motifs. The protein had a predicted mass of real-time reverse transcriptase-PCR, in 153 female patients 306 kDa and contained four homeodomains and 17 zinc finger with invasive carcinoma of the breast. ATBF1-A protein motifs. In 1995, a second ATBF1 cDNA was isolated (5). It was expression was also determined by immunohistochemistry called ATBF1-A, contained 23 zinc finger motifs and was 3.3 kb from available 90 cases of paired tissues. An association was longer than the previously reported clone, now identified by the sought between ATBF1-A expression and various clinico- term ATBF1-B. Analysis of the expression and function of this pathologic factors. ATBF1-A gene has subsequently shown that it plays a role in the Results: ATBF1-A mRNA was expressed at significantly differentiation of a variety of cell types (5, 6). It was found that higher levels in breast cancer patients with no axillary lymph AFP expression is inhibited by ATBF1-A and that the absence of node involvement, with small tumors measuring <2 cm and in ATBF1-A is a distinct feature of AFP-producing gastric cancer estrogen receptor-A–positive tumors. By contrast, no rela- cells, which are characterized by extremely high malignancy (7). tionship was found between ATBF1-A mRNA expression and ATBF1-A protein has also been reported to bind to c-Myb and ATBF1-A protein expression, and also no relationship was repress its transcription activity, which may result in changes in found between ATBF1-A protein expression and any of the cell growth and differentiation (8). Recently, it was revealed that other clinicopathologic factors. Patients expressing high levels in AFP-producing gastric cancer cells treatment with mitomycin of ATBF1-A mRNA tended to have a better prognosis than can induce ATBF1 gene expression, which enhances the promoter activity of the p21 (Waf1/Cip1) gene and the activation of p21 (Waf1/Cip1) promoter would lead to the arrest of AFP- producing gastric cancer cell growth (9). These results together Received 6/27/04; revised 9/1/04; accepted 10/14/04. may imply that altered gene expression or biological activity may Grant support: Ministry of Education, Science and Culture of Japan be associated with malignant transformation (10). The human grant-in-aid for scientific research 14370362 and found for the ATBF1 transcription factor gene has been assigned to chromo- communication between Nagoya citizen and foreign students (Z. Zhang). some 16q22.3-q23.1 (11). Our previous and others studies The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked showed that a loss of heterozygosity on the long arm of advertisement in accordance with 18 U.S.C. Section 1734 solely to chromosome 16 is one of the most frequent genetic events in indicate this fact. breast cancer, which implies the presence of a tumor suppressor Requests for reprints: Hirotaka Iwase, Department of Breast and gene (12, 13). This led us to hypothesize that there was a link Endocrine Surgery, Nagoya City University Hospital, Kawasumi 1, Mizuho-ku, Nagoya 467-8601, Japan. Phone: 52-853-8231; Fax: between levels of ATBF1 expression and the metastatic potential 52-853-6440; E-mail: [email protected]. of breast cancer and also, therefore, the prognosis of these D2005 American Association for Cancer Research. patients. The regulation of AFP gene by ATBF1-A as shown in

AFP-producing gastric cancer also gives us a hint that ATBF1-A (7) and to generate standard curves, which was kindly provided gene also plays some role in other malignant tumors such as by Dr. N. Harada (Division of Molecular Genetics, Institute for breast cancer. It is well known that AFP production decrease Comprehensive Medical Science, Fujita Health University, rapidly after birth and the protein is rarely found in adult tissue, Toyoake, Aichi, Japan; ref. 16). mRNA was isolated using the and elevated levels of AFP in adults, which occur following TRIZOL reagent (Life Technologies, Inc., Tokyo, Japan) the reactivation of the gene, are indicative of several disease according to the manufacturer’s instructions. Reverse transcrip- conditions, most notably malignant liver cancer. Therefore, tion reactions were done as previously described (17). understanding the system of AFP gene regulation might lead us Primers and Probes. We conducted Blast searches to a greater appreciation of the process involved in carcinogenesis (Genbank) to confirm the specificity of the nucleotide sequences and also the general principles concerned in cell differentiation. chosen for the primers and probes and to confirm the absence of At present, the expression of ATBF1-A and its clinicopath- DNA polymorphism. To avoid detection of contaminating ologic importance remains unclear in breast cancer. Through the genomic DNA, the primers were located at exon 2 and exon 3. use of quantitative real-time reverse transcriptase-PCR, done The specific oligonucleotide primers were synthesized according using LightCycler, and inmmunohistochemistry we report here to published information on the ATBF1-A gene as follows: sense on a correlation between levels of ATBF1-A expression and primer, 5V-GGACGCCCAGTTCATGATG-3V (3319-3337) and several clinicopathologic factors, in samples taken from 153 antisense primer, 5V-TCGCCCAGGTTCATCAGCT-3V (3468- female patients with invasive carcinoma of the breast. To our 3450). The PCR product size is 150 bp. The donor probe 5V- knowledge, this is the first report of the quantitative expression of GCCATGACGCCTGCTCTAGTGGG-3V has a fluorescein label the ATBF1-A gene and protein in breast cancer. at its 3V end. The acceptor probe 5V-GGTGAGATCCCCCCTA- GACATGCG-3V has LC Red 640 at its 5V end. To ensure the fidelity of mRNA extraction and reverse MATERIALS AND METHODS transcription, all samples were subjected to PCR amplification Patients and Tumor Samples. Primary invasive breast with oligonucleotide primers and probes specific for the consti- carcinoma specimens were obtained, by surgical excision, from tutively expressed gene glyceraldehyde-3-phosphate dehydroge- 153 female patients at the Department of Breast and Endocrine nase (GAPDH) and normalized. GAPDH primers were as follows: Surgery, Nagoya City University Hospital, Nagoya, Japan forward primer, 5V-AAATCAAGTGGGGCGATGC TG-3V and between 1992 and 2000. Informed consent was obtained from reverse primer, 5V-GCAGAGATGATGACCCTTTTG-3V. The all patients before surgery. The ethics committee of Nagoya City sequences of the GAPDH probes used for real-time LightCycler University Graduate School of Medicine, Nagoya, approved the PCR were 5V-AGAAGGCTGGGGCTCATTTGCAGGG-3V and study protocol. The median age of the patients was 53 years 5V-GTCCACTGGCGTCTTCACCACCATG-3V. All primers and (range, 34-88 years). The patients’ tumors were classified using probes were purchased from the Japanese Gene Institute the International Union Against Cancer staging system as (Saitama, Japan). follows: 40 cases were classified as stage I, 95 cases as stage Real-Time Reverse Transcriptase-PCR. Real-time re- II, 16 cases as stage III, and 2 cases as stage IV. As postoperative verse transcription-PCR was done using a LightCycler (Roche adjuvant treatment, tamoxifen was given to patients with estrogen Molecular Biochemicals, Mannheim, Germany) as previously receptor-a (ERa) and/or progesterone receptor (PR)–positive reported (18). The PCR reaction was carried out in a final tumors. Depending on tumor stage, the following chemotherapy volume of 20 AL containing 2.4 AL of 25 mmol/L MgCl2, regimens were given: oral 5-fluorouracil, CMF (100 mg p.o. 0.5 AL of 20 pmol/AL sense primer and antisense primer, cyclophosphamide, days 1-14; 40 mg i.v. methotrexate, days 1 0.4 AL of 10 pmol/AL donor and acceptor probe, 2 AL PCR and 8; 500 mg i.v. 5-fluorouracil, days 1 and 8), or CEF (500 mg master mix, 1.5 AL cDNA, made up to 20 AL with water. cyclophosphamide; 60 mg epirubicin; 500 mg 5-fluorouracil; After an initial denaturation step at 95jC for 60 seconds, every 3 or 4 weeks). Since 1995, postoperative treatment has been temperature cycling was initiated. Each cycle consisted of done with reference to the recommendation of St. Gullen (14). denaturation at 95jC for 0 second, hybridization at 56jCfor After recurrence, patients with ERa- and PR-negative tumors 5 seconds, and elongation at 72jC for 6 seconds. The were treated with CMF, CEF, and taxanes. Patients with hormone fluorescence signal was acquired at the end of the hybridiza- receptor–positive tumors and nonvisceral metastases were tion step. A total of 55 cycles were done. Cycling conditions treated with endocrine therapy, such as antiestrogens, aromatase for GAPDH were as follows: initial denaturation at 95jCfor inhibitors, and medroxyprogesterone acetate. Patients were 60 seconds, followed by 50 cycles at 95jC for 0 second, followed postoperatively, every 3 months. The median follow- 60jC for 5 seconds, and 72jC for 8 seconds. up period was 61 months (range, 48-144 months). Standard Curves and Presentation of Results. For each Patients were graded histopathologically according to the PCR run, a standard curve was constructed using serial dilutions modified Bloom and Richardson method proposed by Elston and of cDNA obtained from the HepG2 cell line. The level of Ellis (15). Samples were snap frozen in liquid nitrogen and expression of ATBF1-A mRNA was given as relative copy stored at À80jC until RNA extraction. numbers normalized against GAPDH mRNA and shown as mean Isolation of Total RNA and Reverse Transcription. F SD. Relative ATBF1 mRNA expression was calculated by the Total RNA from homogeneous breast cancer tissue, which was formula: (ATBF1-A/GAPDH) Â 1,000. microscopically confirmed, was isolated from f500 mg of A nontemplate negative control was included in each frozen specimen. Total RNA was also isolated from one flask of experiment. All of the nontemplate negative controls, the human hepatoma HepG2 cell line for use as a positive control the standard cDNA dilutions from the HepG2 cell line, and

the tumor samples were assayed in duplicate. All of the RESULTS patient samples with a coefficient of variation for gene mRNA Patient Demographics and Tumor Characteristics. copy number data >10% were retested using the method of Clinical characteristics are summarized in Table 1. The amount Bieche et al. (19). of ATBF1-A mRNA expressed in the samples from the Immunohistochemical Staining of ATBF1-A Protein. 153 patients ranged from 0 to 1975 relative copy numbers Immunohistochemical staining of ATBF1-A protein from (mean, 438). available 90 cases of paired tissues was done as previously The Level of Expression of ATBF1-A mRNA Correlated reported (20). In brief, tissue sections were deparaffinized and with Axillary Lymph Node Metastasis and Tumor Size. The rehydrated and boiled in target retrieval solution (DAKO, level of ATBF1-A mRNA expression in patients lacking axillary Carpinteria, CA) to improve staining. All sections were lymph node metastases (508 F 464) was significantly higher incubated with methanol containing 0.3% H2O2 1.0% sodium than the level in the group with axillary lymph node metastases azide to block endogenous peroxidase activity and were (317 F 375; P = 0.0007). Additionally, it was found that the level incubated with rabbit antiserum for ATBF1-A (at 1:10,000 of ATBF1-A mRNA in the group of patients with tumors dilution) overnight at 4jC. Immunoreactive products were measuring <2 cm (494 F 386) was higher than in the group detected using DAKO Envision+, then visualized after adding with tumors >2 cm (418 F 460; P = 0.022). However, the level 3,3V-diaminobenzidine as the chromogen. of ATBF1-A mRNA expression was not found to be signifi- Immunohistochemical Staining of ERA and PR. cantly correlated with any other clinicopathologic factors, such Immunostaining of ERa and PR was done as previously as the patient’s age, menopausal status, or histologic grade of described (21, 22). Briefly, the slides were incubated at a the tumor (Table 1). dilution of 1:100, with either anti-ERa primary antibody The Level of Expression of ATBF1-A mRNA Correlated (ER1D5; DAKO, Kyoto, Japan) or anti-PR primary antibody with ERA Protein Expression but not with PR Protein (PgR636; DAKO, Kyoto, Japan), using the streptavidin-biotin Expression. A higher level of ATBF1-A mRNA expression was system (SAB-PO kit, Nichirei, Tokyo, Japan) according to the also found in the ERa-positive group of patients (486 F 478) than manufacturer’s instructions. The immunostaining of ATBF1-A, that in ERa-negative group (337 F 350; P = 0.042). However, ERa, and PR was subjectively assessed by two independent there was no difference in the level of ATBF1-A mRNA investigators (Z.Z. and H.I.), and discordant results were expression between the PR-positive and PR-negative groups of resolved by consultation with a third investigator (H.Y.). patients (Table 1). Immunohistochemical scoring of ATBF1-A was scored by Patients whose Tumor Expressed Higher Levels of immunohistochemical score as previously described (21). The ATBF1-A mRNA Tended to Have Better Disease-Free and expression of ERa and PR was scored by assigning a proportion Overall Survival. To identify a clinically meaningful cutoff score and an intensity score according to Allred’s procedure (23). point for a level of ATBF1-A mRNA expression that could be Statistical Analysis. The nonparametric Mann-Whitney used in disease prognosis analysis, various levels of ATBF1-A U test was used for the statistical analysis of the association mRNA expression were tested using the Kaplan-Meier method between ATBF1-A expression and clinicopathologic factors. and verified by the log-rank (Cox-Mantel) and Breslow- Disease-free survival (DFS) and overall survival curves were Gehan-Wilcoxon tests. When analyzing DFS the cutoff point generated by the Kaplan-Meier method and verified by the log- for the level of ATBF1-A mRNA was set at 396: patients with a rank (Cox-Mantel) and Breslow-Gehan-Wilcoxon tests. Cox’s high level of ATBF1-A mRNA expression (912 F 445, n = 53) proportional hazard model was used for univariate and tended to have a better prognosis than those with a low multivariate analyses of prognostic values. Differences were expression (187 F 107, n = 100); log-rank (Cox-Mantel) test, considered significant when a P < 5% was obtained. P = 0.005; Breslow-Gehan-Wilcoxon test, P = 0.006 (Fig. 1A).

Table 1 ATBF1-A mRNA expression and clinicopathologic factors in breast cancer No. patients ATBF1 mRNA (mean F SD) Mann-Whitney U test (P) Age (y) >50 102 473 F 452 NS V50 51 367 F 415 Menopausal status Post 93 478 F 457 NS Pre 60 376 F 412 n(À) 97 508 F 464 0.0007* (+) 56 317 F 375 t <2 cm 40 494 F 386 0.022* z2cm 113 418 F 460 ERa (+) 104 486 F 478 0.042* (À) 43 337 F 350 PR (+) 80 421 F 451 NS (À) 60 449 F 451 HG 1.2 106 430 F 429 NS 3 47 456 F 473 NOTE: Abbreviations: n, axillary lymph nodes; t, tumor size; HG, histological grade. *P < 0.05.

Univariate and Multivariate Prognostic Analysis of ATBF1-A mRNA Expression in Breast Cancer for DFS and Overall Survival. From the limited 153 cases of breast cancer patients, it was found that ATBF1-A mRNA expression is an independent prognostic factor for DFS (Table 2) but not for overall survival (Table 3). ATBF1-A Protein Expression in Breast Cancer and its Correlation with Clinicopathologic Factors. Specific ATBF1- A protein staining was found in the nucleus of some normal epithelial cells (Fig. 2A) and in the cytoplasm of the majority of breast cancer cells (Fig. 2B). We did not find any relationship between ATBF1-A protein expression and the clinicopathologic factors and we also did not find the correlation between ATBF1- A mRNA expression and protein expression (data not shown).

DISCUSSION ATBF1-A and ATBF1-B transcripts are generated by alternative promoter usage combined with alternative splicing. ATBF1-A is a large transcription factor containing four homeodomains and 23 zinc finger motifs; the deduced protein is 404 kDa. It differs from ATBF1-B by an extra 3.3-kb sequence at the 5V end and a 920-amino-acid extension at the NH2 terminus (5). Previous studies on the functions of ATBF1- A showed that the absence of ATBF1-A is responsible for AFP gene expression in gastric cancer, and the absence of ATBF1-A is a distinct characteristic of AFP gene expression gastric cancer and might be important for its highly malignant nature (7). These previous studies also showed that ATBF1-A plays a role in the maintenance of the undifferentiated state of myoblasts, and its down-regulation is a prerequisite for the initiation of the terminal differentiation of murine C2C12 Fig. 1 Statistical analysis of ATBF1-A mRNA expression levels and myoblasts (6). It also showed that ATBF1-A is expressed in the DFS and overall survival using the Kaplan-Meier method. A, DFS was crypts and the bases of the villi of the small intestine and significantly better in the patients with higher levels of ATBF1-A mRNA negatively regulates transcription of brush-border enzyme gene, expression in their tumors (912 F 445) compared with those with lower aminopeptidase-N and proposed that ATBF1-A regulating levels of expression [187 F 107; log-rank (Cox-Mantel) test, P = 0.005; Breslow-Gehan-Wilcoxon test, P = 0.006]. B, patients with tumors aminopeptidase-N gene expression in the crypt-villus axis of expressing higher levels of ATBF1-A mRNA also showed better overall the small intestine is a landmark of enterocyte differentiation survival than those with lower levels of expression [log -rank (Cox- and maturation (24). Taken together, all these observations Mantel) test, P = 0.02; Breslow-Gehan-Wilcoxon test, P = 0.04]. helped formulate the proposal that altered expression or biological activity of ATBF1-A may be associated with malignant transformation (10). When analyzing overall survival, the same method was adopted. However, the expression of AFBF1-A and its clinico- When the cutoff point for the level of ATBF1-A mRNA was pathologic function remains unclear in breast cancer. In the set at 396: patients with a high level of ATBF1-A mRNA present study, it was found that ATBF1-A mRNA was expression (912 F 445, n = 53) tended to have a better prognosis expressed at significantly higher levels in breast cancer than those with a low expression (187 F 107, n = 100); log-rank patients with no axillary lymph node involvement, with small (Cox-Mantel) test, P = 0.02; Breslow-Gehan-Wilcoxon test, tumors measuring <2 cm, and with ERa-positive tumors. P = 0.04 (Fig. 1B). However, no relationship was found between ATBF1-A mRNA

Table 2 Prognostic factors in 153 cases of breast cancer compared with disease-free survival Variable Univariate Mutivariate PPRelative risk (95% confidence interval) Lymph nodes 0.0005 0.0569 0.469 (0.215-1.023) Tumor size 0.0372 0.3861 0.514 (0.114-2.318) ER 0.0007 0.0578 2.239 (0.974-5.150) PR 0.0013 0.0424 2.447 (1.031-5.804) ATBF1-A mRNA 0.0110 0.0383 4.706 (1.087-20.374)

Table 3 Prognostic factors in 153 cases of breast cancer compared with overall survival Variable Univariate Multivariate PPRelative risk (95% confidence interval) Lymph nodes 0.0019 0.0225 0.341 (0.135-0.859) ER 0.0064 NS PR 0.0014 NS ATBF1-A mRNA 0.0325 NS expression and any of the other clinicopathologic factors under ERa-negative tumors (P = 0.042) suggests that levels of this study (i.e., the patient’s age, menopausal status, histologic grade transcription factor might have potential as an indicator of of the tumor, or PR status). Patients with high levels of expres- responsiveness to endocrine therapy. However, this needs to sion of ATBF1-A mRNA tended to have a better prognosis than be verified in a large cohort of endocrine therapy responders those with low expression. Furthermore, the highly significant and nonresponders patients. In addition, ATBF1-A mRNA difference in ATBF1-A expression between the lymph node expression could have implication as a prognostic indicator positive and lymph node negative groups (P = 0.0007) suggests for breast cancer progression as shown in this study by that, in breast cancer, ATBF1-A levels may serve as a marker or univariate and multivariate analyses. The correlation shown in indicator of lymph node metastasis. However, this needs to this study, between increased ATBF1-A mRNA expression be confirmed at the protein level in a larger group of patients with and better prognosis for a patient’s DFS and overall survival, a more homogeneous stage because it is the protein not the indicates that there are similarities in the nature of the mRNA is predictive. The significantly higher level of ATBF1-A ATBF1-A gene seen in breast and AFP-positive gastric cancer. expression seen in ERa-positive tumors compared with This possible similarity is deduced from the fact that in AFP- positive gastric cancers, as discussed above, negative ATBF1- A expression is associated with extremely high malignancy. The reason for the significant correlation between increased ATBF1-A mRNA expression and better prognostic clinicopathologic factors in this study remains unknown. The human ATBF1 transcription factor gene has been assigned to chromosome 16q22.3-q23.1 (11). In previous studies, we and others have shown that loss of heterozygosity on the long arm of chromosome 16 is one of the most frequent genetic events in breast cancer, which implies the presence of a tumor suppressor gene (12, 13). Further study to examine loss of heterozygosity on the ATBF1-A gene is needed to clarify its relationships with the clinicopathologic factors as shown in the present study. It is also of intriguing but highly preliminary to notice that the exporting of ATBF1-A protein, as shown in the present study by immunohistochemical, from nucleus of normal epithelial cells to the cytoplasm of breast cancer cells. The modulating of ATBF1-A protein shuttling between nucleus and cytoplasm compartment remains unknown and the function of ATBF1-A protein presented in the cytoplasm of breast cancer cells also remains unclear. We postulate that the positive staining of ATBF1-A in the cytoplasm of breast tumor cells may means that the proliferation status of tumor cells, which was supported by our unpublished observation that in rat breast feeding stage the positive staining is in the normal epithelium cytoplasm and after stopping of feeding for 10 days the cytoplasm staining decrease greatly.4 However, this also calls for further studies. In conclusions, in breast cancer, levels of ATBF1-A may serve as a predictive indicator of lymph node metastasis. The results of this study also imply that ATBF1-A gene expression

Fig. 2 Representative microscopic views of ATBF1-A staining using a rabbit antiserum for ATBF1-A (at 1:10,000 dilution). A, ATBF1-A staining was found in the nucleus of some normal epithelial cells. B, ATBF1-A staining was also found in the cytoplasm of the majority of cancer cells (original magnification Â400) 4 Y. Miura et al., unpublished data.

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Zhenhuan Zhang, Hiroko Yamashita, Tatsuya Toyama, et al.

Clin Cancer Res 2005;11:193-198.

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