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Down-Regulated Xanthine Oxidoreductase Is a Feature of Aggressive Breast Cancer

Authors' Affiliations: ¹ Research Program for Developmental and Reproductive Biology and Hospital for Children and Adolescents, Biomedicum Helsinki, University of Helsinki; ² Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland; and ³ Institute of Medical Technology, University of Tampere, Tampere, Finland

Requests for reprints: Nina Linder, Research Program for Developmental and Reproductive Biology, Room B524b, Biomedicum Helsinki, University of Helsinki, P.O. Box 63 (Haartmaninkatu 8), FIN-00014 Helsinki, Finland. Phone: 358-9-4717-1976; Fax: 358-9-4717-1947; E-mail: nina.linder{at}hus.fi.

	Abstract

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Purpose: Xanthine oxidoreductase (XOR) is a key enzyme in the degradation of DNA, RNA, and high-energy phosphates and also plays a role in milk lipid globule secretion. Given the strong and regulated expression of XOR in normal breast epithelium, and the previously shown alterations of its expression in experimental tumorigenesis, we hypothesized that XOR may be differentially expressed in breast cancer.

Experimental Design: XOR expression was analyzed by immunohistochemistry in tissue microarray specimens of 1,262 breast cancer patients with a median follow-up of 9.5 years.

Results: Expression of XOR was moderately decreased in 50% and undetectable in another 7% of the tumors. Decreased XOR expression was associated with poor histologic grade of differentiation, ductal and lobular histologic types, large tumor size, high number of positive axillary lymph nodes, and high cyclooxygenase-2 expression, but not with estrogen or progesterone receptor status, Ki-67, p53, or ERBB2 amplification. Absence of XOR expression was associated with unfavorable outcome, and patients with no XOR expression had more than twice the risk of distant recurrence as compared with those with a moderately decreased or normal expression (hazard ratio, 2.21; P < 0.0001). This was also true in patients with node-negative disease (hazard ratio, 2.75; P < 0.0001) as well as in patients with small (1 cm) tumors (hazard ratio, 3.09; P = 0.027). In a multivariate survival analysis, negative XOR emerged as an independent prognostic factor both in the entire series (P = 0.01) and among patients with node-negative disease (P = 0.0009).

Conclusion: Loss of XOR identifies breast cancer patients with unfavorable prognosis.

Key Words: Xanthine oxidoreductase • breast neoplasms • prognosis • survival analysis

View larger version (15K): [in this window] [in a new window]   Fig. 1. A simplified overview of the pathways leading to the formation of substrates for XOR. Reactions catalyzed by XOR and the purine salvage pathway. HPRT, hypoxanthine phosphoribosyltransferase; cGMP, cyclic GMP.

Despite the evidence of a role for XOR in cancer, the enzyme has been previously studied in only a very limited number of human tumor specimens. We hypothesized that XOR may be differentially expressed in human cancers, breast cancer in particular, because XOR is strongly expressed in the normal resting mammary epithelium. To address this question, we examined the expression of XOR in an unselected nationwide patient series, and analyzed whether the expression of XOR protein is associated with clinicopathologic variables and clinical outcome in breast cancer.

	Materials and Methods

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Patients and preparation of tumor tissue microarrays. Using the files of the nationwide Finnish Cancer Registry, all women diagnosed with breast cancer in 1991 and 1992 were identified. Five well-defined geographic regions, comprising more than 50% of the Finnish population, were selected for the study. The database includes information on clinical and pathologic characteristics extracted from the hospital records and, in addition, data on a series of tumor markers determined from the primary tumor specimens (15, 16). A total of 2,846 patients (93% of all breast cancer patients within the selected regions) with sufficient clinical data available were entered into the database (the FinProg Breast Cancer Database, accessible at http://www.finprog.org). The median follow-up of patients alive at the end of follow-up is 9.5 years (range, 0.2-10.8 years). Routinely fixed paraffin-embedded tumor samples were extracted from the files of pathology laboratories, and histopathologically representative tumor regions were used for preparation of tumor tissue array blocks (17). From the 1,931 tumor samples available, 19 tissue microarray blocks were prepared, each containing 50 to 144 tumor samples. In addition, 20 whole-slide specimens were prepared for evaluation of tumor heterogeneity.

XOR protein expressions in the normal mammary gland (n = 14) and the lactating mammary gland (n = 3) were evaluated in specimens obtained at breast surgery for reduction mammoplasty or suspected cancer.

Immunohistochemistry. The antigen was enhanced in Target Retrieval Solution (pH 6.0; DAKO, Carpentaria, CA) at 95°C to 97°C for 30 minutes on routinely processed paraffin sections. The sections were then treated with 3% hydrogen peroxide and XOR protein was detected using a well-characterized rabbit polyclonal anti-XOR antibody (2, 18). The antibody was diluted 1:50 in Blocking Solution (Powervision, Immunovision, Inc., Daly City, CA), and incubated with the samples (overnight at +4°C). An antimouse-peroxidase polymer (30 minutes at room temperature) and diaminobenzidine as a chromogen (Powervision) were used for visualization. Specificity of the XOR localization was confirmed by staining slides with preimmune serum and without the primary antibodies.

Of the 1,931 tissue core biopsies stained for XOR, 314 either had detached (n = 229; 8%) or did not contain identifiable tumor cells (n = 85; 3%). Cases with in situ carcinoma, distant metastasis at the time of diagnosis, synchronous or metachronous bilateral breast cancer, cases with a history of malignancy other than breast cancer except for basal cell carcinoma or cervical in situ carcinoma, and women who did not undergo breast surgery were excluded. Following these exclusions, 1,262 unilateral, invasive breast carcinomas were eligible for analysis and had an interpretable tissue XOR staining result. Eight hundred seventy-eight patients (70%) were treated with mastectomy and 376 (30%) with breast conserving surgery. Postoperative radiotherapy was given to 731 (59%) patients. Only 474 (37%) of the patients had received systemic adjuvant therapy, and these consisted of 290 (61%) patients who received tamoxifen, 177 (37%) women who were treated with cyclophosphamide, methotrexate, and 5-fluorouracil, and 7 (2%) who were given a combination of chemotherapy and tamoxifen. Adjuvant systemic therapy was given to 9% of the patients with node-negative disease and to 92% of the patients with node-positive disease. Twenty of the excluded samples of ductal carcinoma in situ were separately analyzed to evaluate XOR protein expression in this entity.

Immunostainings for the estrogen receptor, the progesterone receptor, Ki-67 antigen, and p53 protein, as well as chromogenic in situ hybridization for ERBB2 (HER-2) gene amplification, were carried out using established procedures (16), and cyclooxygenase-2 (COX-2) protein was visualized as described elsewhere (19).

Scoring of xanthine oxidoreductase immunostaining. Expression of XOR was evaluated by two of the investigators (N.L. and J.L.). Both investigators were blinded to the clinicopathologic data at the time of XOR expression evaluation. Cytoplasmic and nuclear XOR staining of the tumor cells were scored separately. Cytoplasmic XOR staining intensity was scored as follows: strong = staining comparable to that of the normal epithelial cells; moderate = clearly decreased staining; negative = no staining for the XOR protein in more than 90% of the cancer cells.

Nuclear XOR staining intensity was scored as follows: strong staining; moderate staining; and negative staining. Both strong and moderate stainings of the nuclei represent clearly increased XOR expression as compared with the normal breast.

Cell lines. The established breast cancer cell lines SkBr-3 and MCF-7 were obtained from the American Type Culture Collection (Rockville, MD). The MPE-600 cell line was a gift from Geraldine Brush Cancer Research Institute (San Francisco, CA). The cells were cultured using the recommended culture conditions and resuspended in 50 mmol/L potassium phosphate buffer (pH 7.8).

Xanthine oxidoreductase activity measurements. XOR activity was calculated by using [¹⁴C]xanthine as substrate and separating the product uric acid by high-performance liquid chromatography as described (20).

Statistical analysis. The association between XOR expression and other clinicopathologic factors was analyzed using the ² test. The level of agreement between the observers in scoring of XOR expression was estimated by percent agreement and statistics.

Life-tables were calculated according to the Kaplan-Meier method. Distant disease-free survival (DDFS) was calculated from the date of the diagnosis to the first occurrence of metastases outside the locoregional area, or death from breast cancer in cases with missing data on the date of distant recurrence (n = 31). Deaths due to intercurrent causes were censored. Survival curves were compared with the log-rank test or the log-rank test for trend in case of three or more ordered categories. Multivariate survival analyses were done with the Cox proportional hazards model using a backward stepwise selection of variables, and a P value of 0.05 was adopted as the limit for inclusion of a covariate. The assumption of proportional hazards was ascertained with complementary log plots. All statistical tests are two sided.

	Results

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Xanthine oxidoreductase expression in normal and lactating breast. XOR was strongly expressed in the cytoplasm of all acinar cells in the terminal ducts as well as in the epithelial cells of the larger ducts in all specimens of nonlactating normal breast. Cytoplasmic XOR staining was also seen in endothelial cells of capillaries and arterioles. The cytoplasm of the stromal cells showed weak XOR expression. In the lactating mammary gland, the acinar and ductal epithelial cells were intensely stained for XOR, whereas the endothelial and the stromal cells showed similar staining as in the nonlactating mammary gland (Fig. 2).

View larger version (77K): [in this window] [in a new window]   Fig. 2. XOR antibody stained sections of normal (A and B), and lactating (C) human breast tissues. Ductal carcinoma in situ; normal epithelium (N) and carcinoma cells (Ca; E), and tumor microarray cores with primary invasive breast cancer tissue showing strong (F), moderate (G), and negative (H), and nuclear (I) staining of XOR. Representative control staining of normal breast processed with the preimmune rabbit serum (D). Bar, 25 µm.

Xanthine oxidoreductase activity in human breast cancer cell lines. None of the breast cancer cell lines studied (MCF-7, SkBr-3, and MPE-600) showed XOR activity.

Xanthine oxidoreductase expression in breast cancer. Cytoplasmic XOR was scored into three categories in 1,262 invasive breast carcinomas. The percent agreement between the two independent investigators in allocation of the tumors into the three staining categories was 82%. The corresponding value was 0.71, which can be interpreted as a good level of agreement. All specimens with discordant scores were reevaluated by the two investigators, and the consensus score was used for further analyses.

Forty-three percent (n = 534) of the tumors showed strong staining for cytoplasmic XOR similar to the XOR expression in the normal breast, whereas 50% (n = 634) showed moderate staining, corresponding to a clearly decreased XOR expression, and 7% (n = 93) had no cytoplasmic XOR expression (Fig. 2). In the 20 ductal carcinomas in situ samples analyzed, 50% (n = 10) showed strong XOR expression, 40% (n = 8) were moderate, and 10% (n = 2) were negative. The cytoplasms of the stromal cells were either negative or weakly positive for the XOR protein.

Although most nuclei of the normal breasts did not express XOR, 30% (n = 334) of the breast tumors showed moderate and 21% (n = 227) showed strong nuclear expression (Fig. 2), and only 49% (n = 535) were negative for nuclear XOR.

The heterogeneity of XOR expression was minimal in the 20 whole tumor section slides studied. Therefore, the staining results obtained from the tissue microarray cores were considered as representative for the entire tumor.

Association of xanthine oxidoreductase expression with clinicopathologic variables. Decreased cytoplasmic XOR expression was significantly associated with poor histologic grade of differentiation, ductal and lobular histologic type, high COX-2 expression, high number of metastatic axillary lymph nodes, and large tumor size, whereas no statistically significant association was found between cytoplasmic XOR and age at diagnosis, estrogen receptor or progesterone receptor status, Ki-67 or p53 protein expression, or ERBB2 amplification (Table 1).

Association of xanthine oxidoreductase expression with distant disease-free survival. Decreased cytoplasmic XOR expression was significantly associated with decreased DDFS among the 1,262 breast cancer patients (log-rank for trend, P < 0.0001; Fig. 3). The difference in DDFS between patients with normal (strong staining) versus decreased (either moderate or no staining) cytoplasmic XOR expression was highly significant, but the greatest decrease in survival was seen in breast cancer patients who had no detectable cytoplasmic XOR expression (Table 2). Therefore, the groups with strong and moderate XOR stainings were combined for further survival analyses (Table 2; Fig. 4). Patients with strong or moderate XOR expression had an 8-year DDFS of 76%, whereas those with no XOR expression had a DDFS of only 52% (Table 2).

View larger version (13K): [in this window] [in a new window]   Fig. 3. DDFS of 1,262 patients with breast cancer according to XOR protein expression. ······, strong (n = 535); - - -, moderate (n = 634); —, negative (n = 93). P < 0.0001 (log-rank test for trend).

View larger version (18K): [in this window] [in a new window]   Fig. 4. A, DDFS of 771 patients with node-negative breast cancer according to XOR protein expression. —, moderate to strong* (n = 720); —, negative (n = 51). P < 0.0001 (log-rank test). B, DDFS of 224 patients with breast cancer with a tumor less than 1 cm in diameter according to XOR protein expression. —, moderate to strong* (n = 212); —, negative (n = 12). P = 0.02 (log-rank test). C, DDFS of 775 patients with estrogen receptor–positive breast cancer according to XOR protein expression. —, moderate to strong* (n = 722); —, negative (n = 53). P = 0.0015 (log-rank test). D, DDFS of 352 patients with estrogen receptor–negative breast cancer according to XOR protein expression. —, moderate to strong* (n = 323); —, negative (n = 29). P < 0.0001 (log-rank test). *, there was little difference in patient outcome between strong and moderate XOR staining and, therefore, these groups were combined and compared with the patients with absent XOR in the survival analysis.

In contrast to cytoplasmic XOR expression, nuclear XOR expression showed no statistically significant association with survival. Patients with strong or moderate nuclear XOR expression had an 8-year DDFS of 75% [n = 561; 95% confidence interval (95% CI), 71-79] and those with no nuclear XOR expression had a DDFS of 72% (n = 535; 95% CI, 68-76); (risk ratio, 1.09; 95% CI, 0.86-1.37; P = 0.48).

The DDFS of the patients whose tumor XOR expression could not be analyzed (tissue array cores were detached or lacking tumor cells; n = 314) did not differ from that of the patients who had an interpretable XOR staining result (n = 1,262; P = 0.24).

Multivariate analysis. Absence of cytoplasmic XOR expression was an independent prognostic factor in a Cox multivariate analysis along with the number of positive axillary lymph nodes, primary tumor size, progesterone receptor status, and histologic grade, whereas age, histologic type, and estrogen receptor and ERBB2 status were not retained in the model (Table 3). In patients with node-negative breast cancer who did not receive adjuvant therapy, absence of cytoplasmic XOR expression retained its independent prognostic value in addition to size and grade, whereas XOR expression did not have independent prognostic value among patients with node-positive breast cancer (Tables 4 and 5).

	Discussion

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Patients whose tumor tissue did not contain immunoreactive XOR had about twice as high risk for distant recurrence as women whose cancer expressed at least some cytoplasmic XOR protein. Absence of immunoreactive XOR was relatively uncommon (7% of all tumors), but had independent prognostic significance both in the entire patient series and in the subgroup of axillary node–negative disease. XOR expression was not associated with outcome in patients with node-positive disease, of whom a majority received adjuvant systemic therapy, unlike the women with node-negative disease. Further research needs to be carried out to study whether XOR expression of the tumor may be related to the response to adjuvant therapy.

Little is known about the expression of XOR in different types of human cancer, but the sparse data available suggest that XOR activity may decrease in malignant tumors because XOR expression was low or absent in six hepatocellular carcinomas (21) and in four invasive breast carcinomas studied (22). We found that XOR activity is absent in malignant cell lines originating from human breast carcinoma, including MPE-600 cells which have a relatively well-preserved original karyotype (23). Although a statistically significant association between decreased XOR expression and poor histologic grade was observed in our study, 33% of the poorly differentiated tumors showed strong XOR expression, indicating that dedifferentiation does not invariably lead to loss of XOR. The mechanisms of down-regulation of XOR in cancer remain unknown and might include loss of heterozygosity at chromosome 2p where XOR is located (24), decreased gene promoter activity, increased XOR mRNA degradation, or posttranslational changes.

Purine nucleotides are made available for cells via two routes, either by de novo synthesis from low molecular weight precursors or by reutilization of nucleotides catabolized to purine bases, mainly hypoxanthine. XOR and hypoxanthine phosphoribosyltransferase compete for the substrate hypoxanthine, resulting either in irreversible purine loss, when XOR oxidizes hypoxanthine to xanthine and further to uric acid, or in salvage of the purine ring, when hypoxanthine phosphoribosyltransferase converts hypoxanthine to IMP and further to adenine and guanine nucleotides (Fig. 1). Salvage of the purine ring is six times more efficient in terms of ATP equivalents than de novo purine synthesis, and thus cancer cells with effective shunting of purine bases to the salvage pathway might gain a growth advantage. Some evidence for a shift in the purine anabolic-catabolic balance can be found in studies on rodent tumors in which XOR activity has been found to be decreased (12, 21, 25–27) as compared with the corresponding normal tissues, whereas the activities of hypoxanthine phosphoribosyltransferase (28) and the enzymes involved in purine biosynthesis are increased (25, 29).

Interestingly, no association between XOR expression and the hormone receptor status was found. This is unlike most other cancer biological factors we have investigated in the same breast cancer series, such as p53, Ki-67 antigen, and ERBB2 expression, and suggests that down-regulation of XOR may occur independently of the estrogen and progesterone receptor pathways.

In conclusion, many breast cancer samples stain positively for XOR, but its expression in the cytoplasm is usually less than that found in normal breast acinar and ductal cells. Breast cancers that lack cytoplasmic XOR expression are associated with about a 2.5-fold greater risk for distant metastases than cancers showing strong XOR expression. The reasons why loss of XOR is associated with poor outcome in breast cancer remain unknown. Further studies will elucidate whether tumors lacking XOR respond differently to adjuvant therapy compared with those showing XOR expression.

	Acknowledgments

 
We thank Tiina Lehtimäki, Kaija Holli, Liisa Elomaa, Liisa Pylkkanen, Vesa Kataja, and Taina Turpeenniemi-Hujanen for collecting the clinical and follow-up data.

	Footnotes

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 11/ 8/04; revised 2/17/05; accepted 2/23/05.

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