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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 9  |  Page : 368-374

Breast cancer metastasis suppressor gene, breast cancer metastasis suppressor 1, may be associated with clinicopathological features of breast cancer


1 Department of Oncology, Taizhou Central Hospital, Taizhou 318000, P.R. China
2 Department of Oncology, Luqiao Branch of Taizhou Hospital, Taizhou 318000, P.R. China
3 Department of Infection, Luqiao Branch of Taizhou Hospital, Taizhou 318000, P.R. China

Date of Web Publication29-Jun-2018

Correspondence Address:
Yin Pan
Department of Oncology, Taizhou Central Hospital, No. 999, Donghai Road, Jiaojiang District, Taizhou 318000
P.R. China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.172125

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 > Abstract 

Objective: We aim to investigate whether the breast cancer metastasis suppressor gene, breast cancer metastasis suppressor 1 (BRMS1), is correlated with clinicopathological features of breast cancer or not.
Materials and Methods: Following a stringent inclusion and exclusion criteria, case-control studies related to the association between BRMS1 and breast cancer were selected from articles retrieved by electronic database searches. All statistical analyses were performed by Stata version 12.0 (Stata Corp, College Station, TX, USA).
Results: A total of 12 studies were ultimately included in this meta-analysis. Results of our meta-analysis suggested that BRMS1 protein in breast cancer tissues was significantly lower compared with normal breast tissues (odds ratio [OR] =0.08, 95% confidence interval [CI] =0.04–0.15, P < 0.001). The BRMS1 protein in metastatic breast cancer tissue was lower than that in nonmetastatic breast cancer tissue (OR = 0.20, 95% CI = 0.13–0.29, P < 0.001), and BRMS1 protein in tumor-node-metastasis (TNM) stages 1, 2 was found to be higher than TNM stages 3, 4 (OR = 4.62, 95% CI = 2.77–7.70, P < 0.001). With respect to breast cancer types, BRMS1 protein in all the three major types of breast cancer was lower than the normal tissues. We also found strong correlations between BRMS1 mRNA levels and TNM stage and tumor size.
Conclusion: Our meta-analysis results showed that reduced BRMS1 expression level was significantly associated with clinicopathological features of breast cancer, suggesting that loss of expression or reduced levels of BRMS1 might be a strong indicator of the metastatic capacity of breast cancer, with poor prognosis.

Keywords: Anti-metastasis, breast cancer, breast cancer metastasis suppressor 1, clinicopathological features, invasion, meta-analysis, metastasis, prognosis


How to cite this article:
Lin L, Cai M, Dai Y, Zheng Z, Jiang F, Shi L, Pan Y, Song HB. Breast cancer metastasis suppressor gene, breast cancer metastasis suppressor 1, may be associated with clinicopathological features of breast cancer. J Can Res Ther 2018;14, Suppl S2:368-74

How to cite this URL:
Lin L, Cai M, Dai Y, Zheng Z, Jiang F, Shi L, Pan Y, Song HB. Breast cancer metastasis suppressor gene, breast cancer metastasis suppressor 1, may be associated with clinicopathological features of breast cancer. J Can Res Ther [serial online] 2018 [cited 2019 Dec 6];14:368-74. Available from: http://www.cancerjournal.net/text.asp?2018/14/9/368/172125


 > Introduction Top


Breast cancer accounts for nearly one-third of cancers diagnosed among females in the USA, and are the second leading cause of cancer deaths all over the world.[1] Breast cancer is more common in older women, however, 1 in 200 women would be diagnosed with breast cancer before the age of 40 years.[2] In general, nearly 40% of all the patients with breast cancer experience a recurrence, of which 10–20% are locally metastatic and 60–70% are distant metastases.[3] The established risk factors for breast cancer are age, menopausal status, body mass index, duration of breastfeeding, age at first pregnancy, and postmenopausal hormone use.[4],[5],[6] Distant metastasis is the predominant cause of death in breast cancer.[7] Tumor metastasis is a multi-step process involving disruption of intercellular adhesions and dispersal of single cells from solid tumor, invasion of blood and lymphatic vessels, immunologic escape in circulation, attachment to endothelial cells, extravasation from blood and lymph vessels, and proliferation and induction of angiogenesis.[8],[9] This process is aided by a favorable microenvironment at the primary site as well as at the metastatic sites.[7]

Breast cancer metastasis suppressor 1 (BRMS1), which was first described in 2000, inhibits metastasis but has no effect on the growth of primary tumors.[10] The BRMS1 gene is located at 11q13.1–13.2, a region frequently altered in late-stage breast cancers, and is in close proximity to genomic loci that contains deletions and amplifications commonly observed in breast cancer progression.[11] BRMS1 is also an inhibitor of metastasis in ovarian cancer, bladder cancer, nonsmall cell lung cancer, melanoma, and breast cancer, and metastasis mouse models have demonstrated a high capacity of BRMS1 to inhibit metastasis, recording up to 80–90% metastasis inhibition.[8],[12],[13] Despite these observations of the anti-metastatic potential of BRMS1, the mechanisms by which BRMS1 mediates its anti-metastasis function still remain unknown.[7] In this context, it is also important to thoroughly evaluate BRMS1 association with metastatic breast cancer and for this reason; we performed a meta-analysis based study to test the correlation between BRMS1 expression and the tumor behavior in breast cancers.


 > Materials and Methods Top


Search strategy

A systematic literature search was performed using the PubMed, EBSCO, SpringerLink, Wiley, Ovid, Web of Science, Wanfang Database, China National Knowledge Infrastructure, and VIP Information databases using MeSH and free text search terms (last updated search in October, 2014). All variants of key search terms: Breast cancer and BRMS1 were included. For example, (“BRMS1 protein, human” or “breast-cancer metastasis suppressor 1”) and (“breast neoplasms” or “breast cancer” or “breast carcinoma” or “tumors, breast” or “mammary neoplasms, human” or “carcinoma, human mammary” or “mammary cancer” or “malignant neoplasm of breast” or “malignant tumor of breast” or “cancer of the breast”) was selected to retrieve relevant literatures. In addition, bibliographies of the collected trials and review papers were also examined and searched manually for potentially relevant articles.

Criteria for selecting articles included in this meta-analysis

Studies were included: If (1) The study type of the selected studies was case-control study; (2) study subjects were patients diagnosed with breast cancer and healthy controls; (3) selected studies provided complete data including sample size, age, ethnicity, gender, pathological types, positive expression rate of BRMS1 protein, expression of BRMS1 mRNA, and so on; (4) the extracted studies were published by the same authors, only the complete or latest one was included.

Studies were excluded if they were unrelated topic with BRMS1 and breast cancer; or if the data were incomplete; or if the study was not published in Chinese and English; or if the article was published repeatedly.

Data extraction

According to the inclusion criteria listed above, information was extracted from all the included publications systematically by two investigators. The following data were collected from each individual study:First author, country, language, ethnicity, study design, total numbers and mean age of cases and controls, sample size, pathological types, etc.

Statistical analysis

All the meta-analyses were performed utilizing Stata version 12.0 (Stata Corp, College Station, TX, USA). To evaluate the case-control studies, investigating the association between BRMS1 andclinicopathological features of breast cancer, the standardized mean differences (SMDs), odds ratio (OR), and effect size (ES) with 95% confidence interval (CI) were used. Moreover, Z-test was applied to determine the significance of pooled SMDs. Cochran's Q statistic with a significance level of P < 0.05 and the I2 test (0–100%, values of 40% and 75% were considered to indicate moderate and high heterogeneity, respectively) were used to assess heterogeneity across studies. If P < 0.05 or I2 >50%, there was great heterogeneity among studies, and thereby a random effect model was used; if not, a fixed effect model was performed.[14],[15]


 > Results Top


Literature searching results and baseline characteristics of included studies

One hundred seventy-five articles were initially identified through database searches. Thirty-seven papers remained after excluding duplicates (n = 15), animal studies (n = 24), letters, reviews, meta-analyses (n = 2), and unrelated topic (n = 97). After we excluded noncase-control or cohort study (n = 11), studies not relevant to BRMS1 (n = 6), studies unrelated to breast cancer (n = 7), insufficient information in studies (n = 1), and 12 articles were finally selected for this meta-analysis.[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27] Among the 12 studies, study subjects in 9 trials were Asians, 2 trials were performed in Caucasians, and 1 trial was conducted in mixed. As for country, 8 studies were from China, 1 from Japan, USA, England, and Italy, respectively. The included studies were all published between 2006 and 2014. The expressions of BRMS1 in different breast tissues, lymph node metastasis (LNM) status, tumor-node-metastasis (TNM) stages, tumor size, histological grades, pathological types, estrogen receptor (ER) status, progesterone receptor (PR) status, overall survival (OS), and relapse-free survival (RFS) were compared in this meta-analysis. The sample size of study subjects ranged from 70 to 200. Marker in included studies was protein or mRNA. The baseline characteristics of included studies are shown in [Table 1].
Table 1: Baseline characteristics of included studies

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Breast cancer tissue and normal tissues

Heterogeneity test revealed the lack of heterogeneity in the expression of BRMS1 protein between breast cancer tissues and normal tissues, and thereby a random-effect model was used (P = 0.219, I2 = 32.1%). There was heterogeneity in the expression of BRMS1 mRNA between breast cancer and normal tissues, thus a fixed-effect model was performed (P < 0.001, I2 = 99.5%).

Results of this meta-analysis suggested that the expression of BRMS1 protein in breast cancer tissues was significantly lower compared with normal tissues (OR = 0.08, 95% CI = 0.04–0.15, P < 0.001), while there was no significant difference in the expression of BRMS1 mRNA between breast cancer and normal tissues (OR = −6.46, 95% CI = −17.27–4.34, P = 0.241) [Figure 1].
Figure 1: The expressions of breast cancer metastasis suppressor 1 in breast cancer tissues and healthy tissues. (a) Comparison of BRMS1 positive rate between breast cancer tissue and healthy control; (b) Comparison of BRMS1 mRNA level between breast cancer tissue and healthy control

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Clinicopathological features of breast cancer

The heterogeneity test revealed that there was no heterogeneity in the expression of BRMS1 protein in different LNM status, TNM stages, tumor size, histological grades, and pathological types; therefore, a fixed-effect model was adopted (LNM: P =0.229, I2 = 27.5%; TNM stage: P =0.892, I2 = 0.00%; tumor size: P =0.348, I2 = 10.2%; histological grade: P =0.998, I2 = 0.00%; ductal carcinoma: P =0.466, I2 = 0.00%; lobular carcinoma: P =0.473, I2 = 0.00%; medullary carcinoma: P =0.653, I2 = 0.00%). There was heterogeneity in the expression of BRMS1 mRNA in LNM and TNM stage, thus random-effects model was performed (LNM: P <0.001, I2 = 97.2%; TNM stage: P = 0.003, I2 = 88.7%), while there was no heterogeneity in tumor size, and thereby a fixed-effect model was used (P = 0.697, I2 = 0.00%).

This meta-analysis revealed that the expression of BRMS1 protein in metastatic breast cancer tissue was lower than nonmetastatic breast cancer tissue (OR = 0.20, 95% CI = 0.13–0.29, P < 0.001), and the expression of BRMS1 protein in TNM stage 1, 2 was higher than TNM stage 3, 4 (OR = 4.62, 95%CI = 2.77–7.70, P < 0.001). Besides, BRMS1 protein expression level was not significantly associated with tumor size and histological grade (tumor size: OR = 0.92, 95% CI = 0.63–1.35, P = 0.673; histological grade: OR = 1.33, 95% CI = 0.87–2.02, P = 0.190) [Figure 2]. In addition, the expression of BRMS1 protein in the three types of breast cancer tissues were all lower than the normal tissues (ductal carcinoma: OR = 0.10, 95% CI = 0.04–0.22, P < 0.001; lobular carcinoma: OR = 0.09, 95% CI = 0.04–0.23; P < 0.001; medullary carcinoma: OR = 0.02, 95% CI = 0.00–0.12, P < 0.001) [Figure 3].
Figure 2: Positive expression rates of breast cancer metastasis suppressor 1 protein in different lymph node metastasis status, tumor size, and histological grades of breast cancer. LN: lymph node; TNM: tumor node metastasis. (a) Comparison of BRMS1 positive rate between LN present and LN absent; (b) Comparison of BRMS1 positive rate between TNM I/II stage and III/IV stage; (c) Comparison of BRMS1 positive rate between big tumor and small tumor; (d) Comparison of BRMS1 positive rate between histological I/II grade and histological III grade

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Figure 3: Positive expression rates of breast cancer metastasis suppressor 1 protin in different pathological types of breast cancer. (a) Comparison of BRMS1 positive rate between ductal carcinoma and healthy control; (b) Comparison of BRMS1 positive rate between lobular carcinoma and healthy control; (c) Comparison of BRMS1 positive rate between medullary carcinoma and healthy control

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This meta-analysis also indicated that the expression of BRMS1 mRNA was negatively correlated with TNM stage and tumor size (TNM stage: OR = 1.65, 95% CI = 0.36–2.93, P = 0.012; tumor size: OR = −0.30, 95% CI = −0.55–-0.05, P = 0.020), while it had no association with LNM status (OR = −1.69, 95% CI = −3.59–0.22, P = 0.083) [Figure 4].
Figure 4: Expression levels of breast cancer metastasis suppressor 1 mRNA in different lymph node metastasis status, tumor node metastases stages, and tumor size. LN: lymph node. (a) Comparison of BRMS1 mRNA level between LN present and LN absent; (b) Comparison of BRMS1 mRNA level between TNM I/II stage and III/IV stage; (c) Comparison of BRMS1 mRNA level between big tumor and small tumor)

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Immunohistochemistry

No heterogeneity existed among studies exploring the correlation between BRMS1 protein expression and PR status, thus a fixed-effect model was used (P = 0.480, I2 = 0.00%). However, there was heterogeneity among studies investigating the associations of BRMS1 protein expression and ER status, and then a random-effect model was applied (P < 0.001, I2 = 89.4%). In addition, no heterogeneity existed across studies investigating the links between the expression of BRMS1 mRNA with the status of ER and PR, and thus, a fixed-effect model was selected (ER: P =0.233, I2 = 29.8%; PR: P =0.348, I2 = 0.00%), while heterogeneity existed among studies related to the positive expression rate of BRMS1 mRNA and ER and PR status, and a random-effect model was utilized (ER: P <0.001, I2 = 97.3%; PR: P =0.004, I2 = 88.0%). The result of this meta-analysis suggested that the expressions of BRMS1 protein and BRMS1 mRNA were not significant correlated with the status of ER and PR as shown in [Figure 5].
Figure 5: Correlation of breast cancer metastasis suppressor 1 expressions with estrogen receptor and progesterone receptor. (a) Comparison of BRMS1 positive rate between ER+ and ER-; (b) Comparison of BRMS1 mRNA level between ER+ and ER-; (c) Comparison of BRMS1 positive rate between ER+ and ER-; (d) Comparison of BRMS1 positive rate between ER+ and ER-; (e) Comparison of BRMS1 mRNA level between ER+ and ER-; (f) Comparison of BRMS1 positive rate between ER+ and ER-

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Prognosis

There was no heterogeneity among studies which investigated the correlation of BRMS1 protein expression with OS and RFS, and thereby a fixed-effect model was performed (OS: P =0.329, I2 = 0.00%; RFS: P =0.488, I2 = 0.00%).

This meta-analysis indicated that there were significant differences in OS and RFS between patients with positive BRMS1 (BRMS1+) and negative BRMS1 (BRMS1) (OS: ES = 0.31, 95% CI = 0.09–0.53, P = 0.006; RFS: ES = 0.39, 95% CI = 0.11–0.67, P = 0.006) [Figure 6].
Figure 6: Overall survival rates and relapse-free survival rates on the correlation between breast cancer metastasis suppressor 1 and breast cancer. (a) Comparison of overall survival rate between BRMS1 positive and BRMS1 negative; (b) Comparison of relapse free survival rate between BRMS1 positive and BRMS1 negative

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 > Discussion Top


The present meta-analysis investigated the correlation between BRMS1 and the clinicopathological features of breast cancer including LNM, TNF stages, tumor size, histological grade, pathological type, ER, PR, OS, and RFS. Invasion and metastasis of malignant tumors not only involve degradation of extracellular matrix but also the interplay between multiple genes such as oncogenes, tumor suppressor genes, and metastasis-regulating genes.[28] At present, nearly 30 metastasis suppressor genes have been recognized in multiple cancers, and loss of their function, through mutations or gene silencing, facilitate metastatic behavior of tumor cells.[8]BRMS1 is an important nuclear protein that differentially modulates the expression of various genes and inhibits metastasis with no effects on the primary tumor growth.[29]

Expressionof BRMS1 is reduced or missing in multiple human tumors. The present study illustrated that BRMS1 protein expression in breast cancer tissue is significantly lower than normal tissue. Moreover, the BRMS1 expression in metastatic breast cancer tissue was lower than nonmetastatic breast cancer tissue, suggesting that invasion and metastasis of breast cancer may be linked to the reduced or missing BRMS1 expression. Potential roles for BRMS1 mediated metastasis suppression in breast cancers might be through altering metastasis-associated microRNA and/or interfering with specific cellular pathways associated with metastasis, including gap junctions, nuclear factor kappa B signaling, phosphoinositide signaling, cell motility and invasion, apoptosis, and tumor cell dissemination, though the exact mechanism remained to be elucidated.[30],[31],[32],[33],[34],[35],[36] Previous studies also reported that BRMS1 decreased lung metastasis in athymic mice when its expression was restored by exogenous expression of BRMS1 in metastatic cell lines from non-small cell lung cancers, ovarian, melanoma, and breast.[37],[38]

In TNM stage 1, 2, we found that the expression of BRMS1 protein was notably higher compared with TNM stage 3, 4, indicating that breast cancer progression might be correlated with low expression of BRMS1 protein. In addition, we also discovered that the expression levels of BRMS1 mRNA were negatively associated with the TNM stage and tumor size, similar to the result with BRMS1 expression and TNM staging.[39] However, contrary to our result which revealed that the expression levels of BRMS1 mRNA was unrelated to LNM, the BRMS1 mRNA expression levels was found to be lower in brain metastasis of breast cancer than primary tumor and it was also reduced in breast tumor compared to matched normal breast tissues.[40],[41] This difference might be due to the limitations of the present study. Finally, there was a significant difference in the OS and RFS between patients with BRMS1+ and BRMS1, suggesting that BRMS1 protein might be a potential prognostic indicator in breast cancer, which is consistent with the study reported by Hanker et al. suggesting low BRMS1 mRNA expression is significantly associated with the poor prognosis of breast cancer.[42]

Limitations of this meta-analysis include small sample size that might adversely affect some of our results. Second, there was also data loss in several studies, which could affect the final result to some extent. Third, our results seemed that BRMS1 protein and mRNA expression were not associated. The expression of BRMS1 protein in breast cancer tissues was significantly lower compared with normal tissues, and there was no significant difference in the expression of BRMS1 mRNA between breast cancer and normal tissues. This was a statistical result and might be caused by the included studies which might differ in the study of BRMS1 protein and mRNA. Finally, no discussion about the expressions of BRMS1 in in-depth classification of breast cancer, such as TNBC and ER+ tumors, was a limitation, which needed further investigation.


 > Summary Top


There was significant correlation between reduced or loss of the expression of BRMS1 and clinicopathological features of breast cancer, suggesting that BRMS1 might be an indicator of the metastatic capacity and its low expression may correlate with the poor prognosis in breast cancer.

Acknowledgment

We are obliged to many colleagues who have shared wisdom with us during the writing of this article. We apologized some whose work was not cited though we have strived to be thorough.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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