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Impacts of Matrix Metalloproteinase-2 Promoter Genotypes on Breast Cancer Risk

CHIH-CHIANG HUNG, CHUNG-LIN TSAI, YU-TING CHIN, YUN-CHI WANG, CHIA-HUA LIU, MENG-LIANG LIN, SHIH-SHUN CHEN, JIE-LONG HE, CHIA-WEN TSAI, CHEN-HSIEN SU, DA-TIAN BAU and WEN-SHIN CHANG
Cancer Genomics & Proteomics September 2024, 21 (5) 502-510; DOI: https://doi.org/10.21873/cgp.20467

Abstract

Background/Aim: Matrix metalloproteinase-2 (MMP-2) has been implicated in the pathogenesis of breast cancer (BC). However, there is limited research on the role of MMP-2 genotypes in BC risk. This study aimed to investigate the associations between two MMP-2 promoter polymorphisms, rs243865 and rs2285053, and BC risk. Materials and Methods: MMP-2 genotypes were analyzed using PCR-based RFLP methodology in a cohort comprising 1,232 BC cases and 1,232 controls. Results: Genotypic frequencies of MMP-2 rs243865 and rs2285053 in controls were consistent with Hardy-Weinberg equilibrium (p=0.3702 and 0.2036, respectively). There were no significant differences in the distribution of rs243865 and rs2285053 genotypes between BC cases and controls (p for trend=0.1602 and 0.2170, respectively). Variant genotypes at rs243865 and rs2285053 appeared to confer a protective effect, although not statistically significant (all p>0.05). Similarly, the variant T allele at rs243865 and rs2285053 showed a non-significant trend towards decreased BC risk (OR=0.84 and 0.89, 95%CI=0.69-1.02 and 0.78-1.02, p=0.0811 and 0.1043, respectively). There was no interaction observed between MMP-2 rs243865 or rs2285053 genotypes and age. Stratified analysis did not reveal significant associations between MMP-2 rs243865 or rs2285053 genotypes and triple-negative breast cancer (TNBC) (p=0.6458 and 0.8745, respectively). Among both TNBC and non-TNBC cases, none of the variant genotypes at rs243865 or rs2285053 showed significant associations with TNBC (all p>0.05). Conclusion: MMP-2 rs243865 and rs2285053 genotypes appear to have a minimal impact on individual susceptibility to BC or TNBC.

Key Words:

Breast cancer (BC) represents the most prevalent malignancy among women, profoundly impacting their physical and mental well-being in clinical settings. In 2020 alone, there were an alarming 2.26 million new cases of BC globally, surpassing lung cancer to become the leading cancer worldwide (1, 2). BC, as the foremost cause of cancer-related deaths in women, exhibits varied effects on quality of life and survival (3). Triple-negative breast cancer (TNBC), comprising 15-20% of BC cases, is characterized by high relapse rates, aggressive metastatic behavior, and low 5-year survival rates (4, 5). Lack of practical biomarkers results in a high recurrence rate of 50% among early-stage (stage I~III) TNBC patients, with 37% mortality within 5 years post-surgery (6). Recently, translational scientists have focused on identifying potential biomarkers for BC, particularly TNBC (7-9).

Due to their collagenase activity, matrix metalloproteinases (MMPs) play a crucial role in the degradation of connective tissue components and basement membranes, thereby influencing processes, such as angiogenesis and metastasis (10, 11). Elevated expression levels of MMPs, including MMP-2 and MMP-9, have been associated with accelerated tumor growth and initiation of invasive and metastatic behaviors (12, 13). The literature consistently links elevated MMP expression levels with BC etiology and metastasis (14, 15). However, conflicting reports suggest lower active MMP-2 levels in BC patients compared to non-cancerous subjects (16, 17).

MMP-2, located on chromosome 16, encodes gelatinase A and targets substrates, such as gelatin, collagen V, and collagen VI (18). Numerous studies have explored the impact of specific MMP-2 polymorphisms on BC risk, particularly focusing on the association with MMP-2 rs243865, though findings have been controversial (19-29). Located at −1,306 in the promoter region, this polymorphic site’s variant T allele has been reported to reduce MMP-2 expression levels (30). Conversely, the biological significance of the variant allele at another promoter polymorphic site, MMP-2 rs2285053 (−735 position), remains unclear. In Tunisian and Iranian populations, the variant T allele of MMP-2 rs2285053 appears to confer a protective effect against BC risk (28, 31).

Previously, we have reported associations between MMP-2 rs243865 genotypes and factors, such as smoking, alcohol consumption, and Helicobacter pylori infection status, influencing individual susceptibility to gastric cancer (32). Both variant TT genotypes at MMP-2 rs243865 and rs2285053 were observed at non-significantly lower frequencies in patients with childhood leukemia (33), prostate cancer (34), and pterygium (35) patients, compared to respective controls. These findings, along with the aforementioned data, suggest that MMP-2 genotype may play a role in BC risk determination. Therefore, our study aimed to evaluate the influence of MMP-2 rs243865 and rs2285053 genotypes (the physical location of MMP-2 genotypes is illustrated in Figure 1) on BC risk specifically within a Taiwanese cohort comprising 1,232 BC cases and 1,232 non-cancerous controls. Additionally, we sought to investigate the potential predictive role of MMP-2 genotypes in TNBC risk.

Figure 1.
Figure 1.

Physical map of matrix metalloproteinase-2 (MMP-2) rs243865 and rs2285053 polymorphic sites.

Materials and Methods

BC and non-cancerous control population. A total of 1,232 patients diagnosed with breast cancer (BC) were recruited from the outpatient clinics of the Department of General Surgery at China Medical University Hospital in Taiwan for this study. All participants were of Taiwanese descent, and detailed procedures, exclusion and inclusion criteria were previously documented (9, 36). Clinical characteristics, including histological details, were determined by expert surgical teams. Breast cancer tissue slides were independently reviewed and scored by at least two pathologists. Estrogen receptor (ER), progesterone receptor (PR), and HER-2/neu immunoassay positivity was defined by nuclear staining in at least 10% of neoplastic cells. A Ki67 labeling index exceeding 30% was considered positive. HER-2/neu results adhered to guidelines set by the American Society of Clinical Oncology and the College of American Pathologists (37). All patients voluntarily participated, completed a self-administered questionnaire, and provided peripheral blood samples. As controls for the study, 1,232 age-matched healthy volunteers were randomly selected initially from the Health Examination Cohort of the hospital. Exclusion criteria for the control group included previous malignancies, metastatic cancers of other or unknown origins, and any familial or genetic diseases. Both groups completed a brief questionnaire that included lifestyle habits. Our study was approved by the Institutional Review Board of China Medical University Hospital (DMR-99-IRB-108), and written informed consent was obtained from all participants. Both cases and controls were of Taiwanese origin, and key demographic characteristics of the population are summarized in Table I.

View this table:
Table I.

Demographics of the 1,232 breast cancer patients and the 1,232 healthy controls.

MMP-2 genotyping methodology. Peripheral blood samples were collected from all participants and their DNA was extracted within 24 h, following our established protocol (38-40). Genotypes for MMP-2 rs243865 and rs2285053 were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. Primer sequences specific to MMP-2 genotyping were designed and optimized by the Terry Fox Cancer Research Lab (35), and PCR conditions were set according to previously published protocols (32, 41). PCR products were digested with Xsp I and Hinf I overnight for MMP-2 rs243865 and rs2285053, respectively, and genotyping profiles were identified by 3% agarose gel electrophoresis. Each sample’s genotyping was independently and blindly repeated by at least two researchers, with all procedures yielding consistent results showing 100% concordance.

MMP-2 statistical analyzing methodologies. The Hardy-Weinberg equilibrium in the non-cancerous control group was assessed using a chi-square test for goodness-of-fit. The age distribution differences between the BC cases and non-cancerous control groups were presented as mean±standard deviation (SD), and statistical comparisons were performed using unpaired Student’s t-test. Pearson’s chi-square test with Yates’ correction (when all analyzing cells >5) or Fisher’s Exact test (when any analyzing cell ≤5) was utilized to evaluate the differential distribution of MMP-2 genotypes. Associations between MMP-2 genotypes and BC risk were assessed through odds ratios (ORs) with corresponding 95% confidence intervals (CIs) across various stratification analysis models. Statistical significance was considered when p-values were ≤0.05. All statistical analyses were performed using SPSS version 16.0 software (SPSS, Inc., Chicago, IL, USA).

Results

The demographic comparisons of the Taiwan BC and non-cancerous population. Table I presents the comparison of age, age at menarche, age at first childbirth, age at menopause, and TNBC status between 1,232 BC cases and 1,232 non-cancerous controls. Initially, no significant differences were detected between the case and control groups regarding age, age at menarche, age at first childbirth, and age at menopause (all p>0.05). Among the 1,232 BC cases, 194 were identified as TNBC cases (Table I).

The genotypic distributions of MMP-2 genotypes among Taiwan BC and non-cancerous subjects. Table II presents the genotypic distributions of MMP-2 rs243865 and rs2285053 among 1,232 non-cancerous controls and 1,232 BC cases. Initially, the frequencies of MMP-2 rs243865 and rs2285053 genotypes among the non-cancerous controls were consistent with Hardy-Weinberg equilibrium (p=0.3702 and 0.2036, respectively). Regarding MMP-2 rs243865, no significant differential distribution was observed between the BC and non-cancerous control groups (p for trend=0.1602). Specifically, carriers of the MMP-2 rs243865 heterozygous variant CT and homozygous variant TT genotypes exhibited 0.87- and 0.55-fold risks for BC, respectively, compared to those carrying the wild-type CC genotype (95%CI=0.71-1.07 and 0.24-1.24, p=0.2137 and 0.2062, respectively). Additionally, individuals with the CT or TT genotype showed an 0.85-fold risk for BC compared to those with CC genotypes in the dominant model (95%CI=0.69-1.04, p=0.1292). Regarding MMP-2 rs2285053, similarly, no variant genotype was associated with altered BC risk in any of the examined models (Table II).

View this table:
Table II.

Matrix metalloproteinase-2 rs243865 and rs2285053 genotypes among the 1,232 patients with breast cancer and 1,232 non-cancerous healthy controls.

The allelic frequency distributions of MMP-2 among Taiwan BC and non-cancerous subjects. Allelic frequency distribution analyses were conducted to validate the findings presented in Table II for MMP-2 rs243865 and rs2285053. Consistently, the variant T allele of both MMP-2 rs243865 and rs2285053 showed a non-significant association with altered risk for BC (OR=0.84 and 0.89, 95%CI=0.69-1.02 and 0.78-1.02, p=0.0811 and 0.1043, respectively, Table III).

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Table III.

Allelic frequencies for matrix metalloproteinase-2 rs243865 and rs2285053 among the 1,232 patients with breast cancer and 1,232 non-cancerous healthy controls.

The correlation of MMP-2 genotypes with onset ages in determining BC risk. Genotyping results for MMP-2 rs243865 and rs2285053 were further stratified by age among both cases and controls to investigate the interaction between MMP-2 rs243865 and rs2285053 genotypes and age in relation to BC risk (Table IV and Table V). Heterozygous and homozygous variant genotypes of MMP-2 rs243865 showed no significant association with BC risk in individuals aged both less than and greater than 55 years (OR=0.86, 0.44, 0.89, and 0.76, 95%CI=0.68-1.10, 0.15-1.29, 0.59-1.33, and 0.20-2.86, p=0.2687, 0.1985, 0.6316, and 0.7468, respectively, Table IV). Similarly, MMP-2 rs2285053 genotypes did not exhibit altered BC risk in individuals aged younger or older than 55 years (OR=0.85, 0.96, 0.88, and 0.70, 95%CI=0.70-1.04, 0.64-1.44, 0.63-1.23, and 0.35-1.38, p=0.1355, 0.9163, 0.5157, and 0.3849, respectively, Table V).

View this table:
Table IV.

Matrix metalloproteinase-2 rs243865 genotypes in breast cancer risk after stratification by age.

View this table:
Table V.

Matrix metalloproteinase-2 rs2285053 genotypes in breast cancer risk after stratification by age.

Association of MMP-2 genotypes with TNBC risk. While MMP-2 rs243865 and rs2285053 genotypes did not appear to be associated with BC risk, we explored their potential as biomarkers for predicting TNBC risk. To address this, BC patients were stratified into TNBC and non-TNBC subgroups. The findings indicated no significant association between MMP-2 rs243865 or rs2285053 genotypes and TNBC (p=0.6458 and 0.8745). Among both TNBC and non-TNBC cases, none of the MMP-2 rs243865 or rs2285053 variant genotypes showed a significant association with TNBC (all p>0.05) (Table VI and Table VII).

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Table VI.

Association of matrix metalloproteinase-2 rs243865 genotypes with breast cancer risk stratified with triple-negative breast cancer (TNBC), non-TNBC, or healthy controls.

View this table:
Table VII.

Association of matrix metalloproteinase-2 rs2285053 genotypes with breast cancer risk stratified with triple-negative breast cancer (TNBC), non-TNBC, or healthy controls.

Discussion

As discussed in the introduction, numerous studies have explored the relationship between clinicopathological features of BC and MMP-2 expression. Several studies have reported that MMP-2 expression levels correlate with BC prognosis (42-47). Conversely, a few studies have observed higher MMP-2 expression levels in BC compared to adjacent non-cancerous tissues (48-50). However, Somiari et al. reported on multiple occasions that the active form of MMP-2 exhibits lower expression levels in BC patients compared to non-cancerous controls (16, 17). While proteomic investigations have not conclusively determined the precise role of MMP-2 in BC etiology, it is evident that MMP-2 plays a significant role in BC development and may represent a potential target for anti-tumor therapy. Given the hereditary nature of BC and the critical role of MMP-2 in epithelial-mesenchymal transition (EMT) and metastatic behaviors of cancer cells, investigating the contribution of MMP-2 genotypes to BC susceptibility is warranted.

Several research teams have explored the association between MMP-2 genotypes and BC risk, yielding conflicting and inconclusive results. In 2004, Zhou et al. reported a reduced BC risk among variant CT or TT carriers of the rs243865 polymorphism in MMP-2 within a cohort of 462 BC patients and 509 non-cancerous controls from Beijing, China (19). Subsequently, Roehe et al. conducted a similar investigation among individuals in Brazil in 2007, finding no significant association (21). This lack of association was further supported by Lai et al. in a Swedish cohort the same year (20). In 2008, Delgado-Enciso et al. provided supportive evidence for Zhou’s findings in a smaller study involving 90 BC patients and 96 controls from Mexico (22). Notably, these studies focused solely on the genotypic profiles of the single polymorphic site rs243865 in MMP-2. In 2009, Beeghly-Fadiel et al. expanded their investigation to 39 MMP-2 polymorphisms among 6,066 women from Shanghai, China, identifying associations with two SNPs (rs11644561 and rs11643630), while rs243865 showed no association (23). In 2013, Zagouri et al. analyzed MMP-2 rs243865 in relation to BC risk in subgroups, finding no overall association but observing a favorable association between the rs243865 T allele and disease-free survival and overall survival in a limited sample of 113 cases and 124 controls (25). Yari et al. attracted attention in 2014 by suggesting that TT genotypes of MMP-2 rs2285053 might serve as a novel protective marker for BC risk based on their study involving 98 BC cases and 135 healthy subjects in Iran (31). In our current study, our primary objective was to evaluate the intrinsic effects of MMP-2 on BC risk within a representative cohort from Taiwan. We found no significant associations between the genotypes of two polymorphic sites, MMP-2 rs243865 and rs2285053, and BC risk (Table II and Table III). Our study benefits from a relatively large sample size but warrants validation in diverse populations of various ethnic backgrounds.

Despite the inclusion of a representative sample size in this case-control study, several limitations merit concise discussion. Firstly, longer follow-up periods are necessary to investigate the contributions of MMP-2 rs243865 and rs2285053 genotypes to BC prognosis, including survival duration, metastasis, and recurrence. For example, Zagouri et al. reported that the MMP-2 rs243865 T allele may indicate longer survival periods in a Southern European population (25). Secondly, the lack of measurements for MMP-2 expression profiles at RNA or protein levels hinders genotype-phenotype correlation analyses. Thirdly, the potential involvement of other MMP-2 polymorphisms, such as rs11644561 and rs11643630, in BC risk determination cannot be excluded. Fourthly, understanding the combined effects of MMP-2 with the expression levels of other genes, such as ER and/or TIMP-2, could provide a more comprehensive understanding of BC etiology. TIMP-2, for instance, acts as both an endogenous MMP-2 inhibitor and suppressor of BC cell proliferation and metastasis (51, 52). Notably, in the context of TNBC, Peeney et al. reported that TIMP-2 suppressed TNBC tumor cell proliferation and metastasis (53). In a previous study, we demonstrated that TIMP-2 rs8179090 genotypes were significantly associated with BC risk among younger (≤55 years old) women but not among older (>55 years old) individuals. Additionally, TIMP-2 rs8179090 genotypes were associated with TNBC risk (9). Lastly, similar to the fourth point mentioned above, the effects of genotypes of other MMP and TIMP family members should be considered. Positive associations have been reported for MMP-7 A-181G (54), TIMP-1 rs4898 (55), and negative associations for MMP-1 rs1799705 ([2G]-1607[1G]) (56), MMP-8 -799C/T, Val436Ala, Lys460Thr (57), TIMP-1 rs6609533, and rs2070584 (55).

In summary, our findings do not provide convincing evidence supporting an association between MMP-2 rs243865 or rs2285053 genotypes and altered susceptibility to BC. Furthermore, MMP-2 may not serve prominently as a predictive marker for TNBC. Importantly, although MMP-2 rs243865 and rs2285053 genotypes did not appear to be significant risk factors for BC or TNBC in the Taiwanese population, further studies across diverse populations are warranted to clarify their potential utility in anti-cancer therapy.

Acknowledgements

The Authors are grateful to the Tissue Bank of China Medical University Hospital and doctors/nurses for their excellent sample collection and technical assistance. The technical assistance from Hou-Yu Shih, and Jyun-Peng Tung was very helpful. This study was supported by China Medical University Hospital and Asia University (ASIA-112-CMUH-17) and Taichung Veterans General Hospital (TCVGH-1124801B).

Footnotes

  • Conflicts of Interest

    The Authors declare no conflicts of interest in relation to this study.

  • Authors’ Contributions

    Research design: Chin YT, Hung CC and Tsai CL; patient and questionnaire summaries: Liu CH, Hung CC and Su CH; experimental work: Wang YC, Chin YT, Chang WS, CH SU and Tsai CW; statistical analysis: Lin MC, He JL, Chen SS, and Tsai CL; data clearance and validation: Chin YT, Wang YC, Tsai CW and Chang WS; article writing: Hung CC, Tsai CL, Bau DT and Chang WS; correction of manuscript: Chin YT, Hung CC, Tsai CL, Wang YC, Liu CH, Lin ML, review and revision: Hung CC, Chang WS and Bau DT.

  • Received July 4, 2024.
  • Revision received July 14, 2024.
  • Accepted July 15, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Impacts of Matrix Metalloproteinase-2 Promoter Genotypes on Breast Cancer Risk
CHIH-CHIANG HUNG, CHUNG-LIN TSAI, YU-TING CHIN, YUN-CHI WANG, CHIA-HUA LIU, MENG-LIANG LIN, SHIH-SHUN CHEN, JIE-LONG HE, CHIA-WEN TSAI, CHEN-HSIEN SU, DA-TIAN BAU, WEN-SHIN CHANG
Cancer Genomics & Proteomics Sep 2024, 21 (5) 502-510; DOI: 10.21873/cgp.20467
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