Annals of Oncology Advance Access originally published online on September 24, 2007
Annals of Oncology 2008 19(2):308-314; doi:10.1093/annonc/mdm453
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breast cancer |
Bone morphogenetic protein 7 expression associates with bone metastasis in breast carcinomas
1 Laboratory of Cancer Genetics, Institute of Medical Technology, University of Tampere and Tampere University Hospital
2 Department of Palliative Medicine
3 Department of Pathology, Tampere University Hospital
4 School of Public Health
5 Medical School, University of Tampere, Tampere, Finland
* Correspondence to: Prof. A. Kallioniemi, Institute of Medical Technology, FIN-33014 University of Tampere, Finland. Tel: +358-3-31164125; Fax: +358-3-31174168; E-mail: anne.kallioniemi{at}uta.fi
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Abstract |
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Background: We recently showed that bone morphogenetic protein 7 (BMP7) is overexpressed in primary breast tumors. Here we explored the clinical significance of BMP7 expression in breast cancer.
Materials and methods: This study included 483 breast cancer patients with complete clinicopathological information and up to 15 years of follow-up. Samples contained 241 lobular carcinomas, 242 ductal carcinomas, and 40 local recurrences. BMP7 protein expression was determined using immunohistochemistry.
Results: BMP7 was expressed in 47% of the primary tumor samples and 13% of the local recurrences. The primary tumors expressed BMP7 more often than the corresponding local recurrences (P = 0.004). BMP7 expression was dependent on the tumor subtype; 57% of the lobular carcinomas but only 37% of the ductal carcinomas were BMP7 positive (P = 0.0001). BMP7 expression was associated with accelerated bone metastasis formation (P = 0.040), especially in ductal carcinomas (P = 0.033), and multivariate analysis confirmed that BMP7 is an independent prognostic indicator for early bone metastasis development (P = 0.032).
Conclusion: BMP7 is clearly associated with bone metastasis formation and thus might have clinical utility in identification of patients with increased risk of bone metastasis. This is the first time that bone inducing factor BMP7 has been linked to the bone metastasis process in breast cancer.
Key words: bone metastasis, bone morphogenetic proteins, immunohistochemistry, invasive ductal carcinoma, invasive lobular carcinoma, tissue microarray
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introduction |
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Invasive breast cancers are classically divided into distinct disease entities by histopathological and clinical features [1]. The most common histological subtype is invasive ductal carcinoma (IDC) that represents 80% of all breast carcinomas. Invasive lobular carcinoma (ILC) accounts for the second largest group (5%–15%) and recent reports indicate an increase in its incidence [2, 3]. These two subtypes differ by their growth characteristics. ILC tends to grow as narrow cords and form a swirling and diffuse pattern [1]. The clinical phenotype is also different between these two; IDCs being more aggressive whereas ILCs are more often hormone receptor positive, ERBB2 negative, proliferate more slowly, and metastasize more often to area of abdominal cavity [3]. Taken together, IDC and ILC are clearly different diseases with different phenotypic traits.
Bone morphogenetic proteins (BMP) are extracellular signaling molecules that belong to the transforming growth factor β superfamily [4, 5]. Currently there are over 20 structurally similar family members identified, one of them being BMP7 [6]. BMPs were named for their ability to form bone and cartilage and are now also known to be critical factors during development. They regulate proliferation, differentiation, and apoptosis in many different cell types by altering target gene transcription. The classical signaling pathway is composed of transmembrane serine/threonine kinase receptors and intracellular Smad proteins [7]. BMP ligand binding activates the cell surface receptors that in turn activate the Smad signaling cascade. Active Smad proteins translocate into nucleus where they regulate target gene transcription. BMP signaling pathway is heavily linked with other signaling pathways (e.g. mitogen-activated protein kinase, Wnt, and signal transducer and activator of transcription pathways) as well as multitude of coregulators (extra- and intracellular inhibitors and enhancers). The cross talk with other pathways and the complex network of regulators is probably behind the pleiotropic actions of BMPs. Due to their versatile abilities to modulate cell behavior; BMPs have also been studied in cancer, most frequently using cancer cell lines and increasingly in vivo mouse models. It has become clear that BMPs do indeed have an impact in cancer, but so far most of the studies have led to contradictory results implicating these molecules in both promotion and inhibition of cancer progression [8–14]. Different outcomes have been observed depending on the ligand and the cancer type studied [8–14]. Therefore, the actual role of BMPs in cancer pathogenesis remains unclear. Interestingly, it has been noted that among hereditable diseases, including cancer predisposition syndromes, disturbances in the BMP signaling result in different clinical phenotypes and it is thought that genetic background can explain these differences [15]. Similar phenomenon could equally apply to sporadic forms of cancer.
In breast cancer, the knowledge of BMP functions is incomplete. Our recent expression survey of different BMP ligands highlighted BMP7 as a potential player in breast cancer [16]. In this study, we utilized a unique tumor material to explore whether BMP7 expression is associated with clinical characteristics of breast cancer. Our material included altogether 483 patients with IDC or ILC and complete patient records with up to 15 years of follow-up information. We studied BMP7 expression in primary and recurrent local tumors by immunohistochemistry and determined the possible associations with clinicopathological parameters, primary treatments, recurrence sites, and survival.
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patients
A total of 483 patients were included in this study. These patients are a part of an earlier study where patient identification and data collection has been described [3]. Briefly, all patients diagnosed with invasive lobular breast cancer from years 1990 to 1999 in the area served by the Tampere University Hospital were identified and matched with an IDC patient of same age and year of diagnosis. For the purpose of this study, 483 archival primary tumor samples were collected including 241 ILCs and 242 IDCs (Figure 1). In addition, our study included histologically verified local recurrence samples (n = 40) from these patients.
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All patient records were evaluated and collected into a common database [3]. A complete patient record contained information on clinicopathological features of the tumor (Table 1), primary treatments, recurrences, and survival. Mean age of the patients at operation was 60.6 years (range 31.6–91.2 years). Altogether, 22% of the patients had received hormone replacement therapy (HRT) for at least 2 years at the time of diagnosis, 19% had a record of prior HRT use whereas 59% had never received HRT. In 79 cases, the HRT information was not available. All patients had their primary tumor surgically removed either by mastectomy or segmental resection, both with axilla clearance. Postoperative radiotherapy with adjuvant medication (endocrine treatment and/or chemotherapy) was given for 33% of the patients, 30% received only radiotherapy, 7% only adjuvant medication, 30% of patients was not given any adjuvant treatment and in seven cases primary treatment data were not available. There were 26 (11%) patients in the ILC group and 24 (10%) patients in the IDC group that developed a local recurrence. The total number of patients with distant metastasis was 48 (20%) and 64 (26%) in the ILC and IDC groups, respectively. The sites of distant recurrences are presented in Table 2.
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Patient survival data were updated at the end of February 2005 from the Finnish Cancer Registry, the Finnish Population Register Centre, and the patient records. The mean follow-up period of the patients was 7.3 years (maximum of 15.2 years). The use of patient samples and patient records in this study was approved by the Ethics Committee of Pirkanmaa Hospital District, Ministry of Social Affairs and Health, and National Authority for Medicolegal Affairs.
TMA construction and immunohistochemistry
Tissue microarrays (TMAs) containing samples from 483 formalin-fixed, paraffin-embedded primary tumors and 40 local recurrences were constructed as described [17]. A single core biopsy (with a diameter of 1 mm) was obtained from each tumor from a histologically representative area. Immunohistochemistry was carried out as described [18]. Briefly, TMA slides were deparaffinized and rehydrated, followed by antigen retrieval in a microwave oven (850 W, 10 mM Tris–HCl, 1 mM EDTA, pH 9.0, 2 x 7 min). BMP7 protein expression was detected by BMP7 goat polyclonal antibody (1:150 dilution, sc-9305, Santa Cruz Biotechnology, Heidelberg, Germany). Polyclonal rabbit antigoat immunoglobulin (1:200 dilution, DakoCytomation, Clostrup, Denmark), and ChemMate DAKO EnVision/horseradish peroxidase, Rabbit/mouse (DakoCytomation) with diaminobenzidine as a chromogen were used for visualization. The slides were counterstained with hematoxylin–eosin. BMP7 staining intensity was evaluated from the whole tumor biopsy area by an experienced pathologist (TK). Homogeneous staining of the epithelial cell compartment across the entire tissue specimen was classified as positive. A nonhomogeneous and very weak staining or no staining at all was classified as negative. A normal human kidney was used as a positive (medullary rays) and negative (glomeruli) control [19] to verify both BMP7 antibody specificity and staining quality.
statistical methods
Associations of BMP7 expression with standard clinicopathological parameters and recurrence sites were evaluated using Fisher's exact test. McNemar test was applied to studies of matched pairs of primary tumor and local relapse. The rate of local recurrence and first distant metastases, as well as disease-free time and survival times were analyzed using Kaplan–Meier method. The log-rank test was used to determine the significance of difference between BMP7-positive- and BMP7-negative tumor groups. Cox regression was used in the univariate and multivariate analyses. All statistical analyses were carried out using SPSS program (version 11.01, SPSS Inc., Chicago, IL).
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BMP7 is more often expressed in lobular than ductal carcinomas
BMP7 protein expression could be evaluated in 409 (85%) of the primary breast tumors (Figure 1). The remaining uninformative cases were due to either lost or unrepresentative samples. BMP7 was expressed altogether in 47% of the analyzed primary tumors (Figure 2). BMP7 expression was clearly dependent on the tumor subtype, with 57% of the ILCs expressing BMP7 whereas only 37% of the IDCs were BMP7 positive (P = 0.0001, Figure 1). Hence the effect of BMP7 on clinicopathological parameters was explored separately in these two tumor groups. In the IDC group, BMP7 positivity was associated with higher pathological T stage (P = 0.034, Table 3) whereas no such association was observed among the ILC cases. The majority of BMP7-negative ductal tumors (70%) were classified as pT1, i.e. <20 mm of tumor diameter, whereas only 55% of BMP7-positive tumors belonged to this stage (Table 3). No statistically significant association between BMP7 expression status and other tumor features (pN and pM status, hormone receptors, ERBB2 expression, proliferation activity, histological/nuclear grade, and DNA ploidy status) were detected in neither tumor group. Finally, we also evaluated whether BMP7 expression was linked with the use of HRT. Patients were divided into three groups according to their HRT use (never users, prior users, and current users) but no association between these groups and BMP7 status could be found.
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local recurrent tumors show decreased BMP7 expression
Local recurrences were detected in total of 50 patients. The recurrent tumor sample was obtained from 40 cases and BMP7 expression was successfully determined in 38 (95%) of them. Surprisingly, only 13% of the local recurrences were BMP7 positive, compared with the considerably higher frequency observed in primary tumors (47%, see above). To confirm that this result was not due to small number of relapse samples we next examined BMP7 expression patterns in a subset of 35 patients (18 cases of ILC and 17 IDC) where both the primary and local recurrent tumor had been evaluated. Among these paired specimens, the primary tumors expressed BMP7 significantly more often than the corresponding local recurrences (P = 0.004), with only two of the 18 patients with BMP7-positive primary tumor also showing BMP7 expression in the local recurrence sample (Table 4). The primary tumor subtype did not explain the loss of BMP7 expression. We then explored whether the treatments of these patients received after primary tumor removal could have influenced BMP7 expression pattern in the local recurrence. In the subgroup of 35 patients, postoperative radiotherapy with adjuvant medication was given for 11% of the patients, 29% received only radiotherapy, 11% only adjuvant medication, and 43% of patients were not given any adjuvant treatment, for two patients treatment information was not available. According to statistical evaluation neither postoperative radiotherapy nor adjuvant therapy could explain the loss of the BMP7 expression in the local recurrent tumor. However, it has to be noted that the number of patients in each treatment subgroup was rather small.
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Next, we studied whether BMP7 status was linked with the occurrence of local recurrence. In ductal carcinomas, BMP7 expression seemed to associate with the development of local recurrences since in the BMP7-positive group 17% of the patients and in the BMP7-negative group only 8% had local recurrences (P = 0.065). Similarly, although still not quite reaching statistical significance, BMP7 expression influenced the rate of local relapse formation in patients with IDC. In the BMP7-positive group, 52 (70%) and 22 (30%) patients remained at risk at 4 and 8 years after diagnosis, respectively, whereas in the BMP7-negative group 101 (80%) and 52 (41%) remained at risk (P = 0.054). Among the lobular carcinomas similar tendencies were not detected.
BMP7 expression associates with accelerated bone metastasis
Finally, we evaluated the possible association between BMP7 expression and the occurrence of distant metastasis or patient survival. Patients with BMP7-positive tumor did develop distant metastases slightly more often than those with BMP7-negative tumor (26% versus 21%, Table 2). When evaluated independently according to the metastasis site, a similar trend towards increased number of bone metastases was observed for patients with BMP7-positive tumors (20% versus 14%, Table 2.). Time to event analysis showed that BMP7 expression in the primary tumor clearly and significantly accelerated the rate of bone metastases formation (P = 0.040, Figure 3A). This effect was observed also when ductal carcinomas were analyzed separately (P = 0.033, Figure 3B), but not for lobular carcinomas (P = 0.29, Figure 3C). A multivariate analysis was carried out to study whether well-known prognostic factors (age, pN and pT stage, histological/nuclear grade, hormone receptor statuses, and ERBB2 status) contribute to this finding. This analysis revealed that BMP7 expression in the primary tumor was indeed an independent prognostic factor for accelerated bone metastasis with a risk factor of 2.14 (P = 0.032, Table 5). Finally no associations were detected in overall or breast cancer-specific survival between patients with BMP7-positive- or BMP7-negative tumors in neither ductal nor lobular carcinoma groups.
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discussion |
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BMPs have been an exciting topic of cancer research for the last 10 years. There is increasing evidence that different BMP ligands have diverse functions on cancer cells originating from various tissues [10, 11, 13, 14]. However, in breast cancer the number of studies is still limited and the results as ever paradoxical. Functional studies using breast cancer cell line models show that BMP signaling can decrease or increase cell growth [8, 9], inhibit apoptosis, or stimulate migration of cancer cells or even induce tumor formation in vivo [11, 20]. However, only two studies have explored the consequences of BMP signaling on patient outcome. These studies show that BMP2 expression does not affect the overall or relapse-free survival of patients with ductal breast carcinoma [20] whereas overexpression of BMP receptor IB associates with poor prognosis in ER-positive breast cancer [21].
We and others have previously shown that BMP7 is overexpressed in breast cancer [16, 18, 22]. In this study, we used a large unbiased set of ILCs and IDCs to determine the possible clinical associations of BMP7 overexpression. Comprehensive clinical and follow-up data was available from this material thus allowing us to fully investigate the clinical significance of BMP7. Our study is one of the very few that have explored the influence of BMP signaling on patient survival in breast cancer and is the first and only one that concentrates on BMP7. Our data revealed that BMP7 was markedly more often expressed in ILC than in IDC (P = 0.0001). Among ductal carcinomas, BMP7 expressing tumors were larger than BMP7-negative tumors. It is intriguing that no clinicopathological associations were detected among lobular carcinomas, although this might be due to the high frequency of BMP7 expression (57% of the cases). Schwalbe et al. [22] have previously reported that BMP7 expression correlates with ER and progesterone receptor expression, but we did not find such association. However, differences in tumor materials and more importantly the classification of immunohistochemical staining results could explain these discrepancies. Overall, our data on BMP7 expression patterns provide further evidence that ductal and lobular carcinomas are distinct disease entities with different molecular backgrounds.
We had the opportunity to study also samples from local breast cancer recurrences. Quite peculiarly, BMP7 expression was lost from most of the local recurrences as compared with the corresponding primary tumor. Of the 18 patients who had a BMP7-positive primary tumor and later developed a local relapse, only two had BMP7 expressing local recurrent tumor. This event did not depend on the tumor type, nor did primary treatments seem to have any effect. Unfortunately, we did not have any samples from distant recurrences so that we could have evaluated whether the same loss of BMP7 expression also occurs in metastatic lesions. Development of local recurrence and distant metastases are, however, distinct processes that are likely to require different tumor cell characteristics. Moreover, BMP7 overexpression has been previously reported to exist in metastatic lesions in melanoma and prostate cancer [23, 24].
The most striking results were obtained by examining BMP7 overexpression and distant tumor recurrence. Patients who suffered from BMP7-positive carcinomas developed more rapidly bone metastases. Multivariate analysis further confirmed that BMP7 expression in the primary tumor is an independent prognostic indicator for accelerated bone metastasis formation. Since BMPs have an established ability to induce and modulate bone formation [5], it is conceivable that they are also involved with bone metastasis in cancer. However, it has to be taken into account that the observed association was not extremely strong suggesting that in addition to BMP7 other factors are likely to contribute to the bone metastasis formation. Further studies are thus clearly warranted to fully explore the impact of BMP signaling in the development of bone metastasis. Nevertheless, this is a first time that any BMP, and more specifically BMP7, has been linked to the bone metastasis process in breast cancer.
Most of the previous evidence on BMPs contribution to the metastatic process comes from prostate cancer that has also a similar propensity to form bone metastases [25]. Overexpression of noggin, a BMP signaling inhibitor, decreased the size of osteolytic lesion in a mouse model of prostate cancer [26]. BMP6 in turn induced the osteoblastic activity of prostate cancer cells [27]. Based on these studies BMPs have a role in prostate cancer bone metastasis. In breast cancer, a well-known target gene of BMP7, named RUNX2 [28], has been associated with metastatic disease [29]. Moreover, it has been shown that RUNX2 stimulates the formation osteolytic lesions in in vivo breast cancer model [30]. Taken together, it is plausible that overexpression of BMP7 might lead to transcriptional activation of RUNX2 and thereby influence the formation of bone metastases in breast cancer.
Our findings might have potential clinical significance. Bone metastases are occasionally hard to detect due to diagnostic limitations [31]. Moreover, biphosphanates have been shown to reduce bone metastasis progression in breast cancer, when used as adjuvant therapy [32]. Determining BMP7 status in primary tumors could help to identify patients who are at higher risk to develop early bone metastasis and would thus benefit from biphosphanate treatment.
In conclusion, our data reveal that BMP7 expression is dependent on the histological tumor subtype in breast cancer. Interestingly, during local regrowth of a tumor BMP7 expression is commonly lost. Most importantly, we here demonstrate for the first time that BMP7 overexpression is indeed an independent prognostic indicator for accelerated bone metastasis formation in breast cancer, even though BMP7 expression alone might not explain the entire bone metastasis process. Finally, BMPs are part of a complex signaling network emphasizing the fact that it is crucial to understand the molecular milieu where BMP7 is functioning since it is likely to have a significant influence on cancer cell behavior.
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funding |
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Academy of Finland; Finnish Cancer Organizations; Medical Research Fund of Tampere University Hospital.
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Acknowledgements |
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K. Rouhento is thanked for data processing. Technical assistance of J. Leppikangas and K. Rouhento is greatly appreciated.
Received for publication July 3, 2007. Revision received August 9, 2007. Accepted for publication August 10, 2007.
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