Abstract P4-07-09: The Impact of Matrix Metalloproteinase-1 Promoter 1G/2G Polymorphism on Breast Diseases
Authors: Zhou J , Somiari S , Lubert S , Saini J , Kane J , Deyarmin B , Hooke J , Mural R , Shriver C , Brinckerhoff C. 
Published: April 2011

Background: Matrix Metalloproteinase-1 (MMP-1) is a ubiquitously expressed interstitial collagenase. Overexpression of MMP-1 has a role in initiating mammary tumorigenesis by degrading stroma and by releasing growth factors. A single guanine insertion polymorphism in the MMP-1 promoter creates the binding site, 5'-GGAA-3', for the Ets transcription factor, and increases transcription of MMP-1. The MMP-1 2G polymorphism is linked to early onset, increased risk or aggressiveness of several cancers. Its relationship with other potential markers in invasion and metastasis of breast cancer is unknown.

Experimental Design: To study the impact of the 2G polymorphism on breast cancer we analyzed the genotypes of 109 patients (52 invasive breast cancer [IBC], 29 ductal carcinoma in situ [DCIS], 13 atypical ductal hyperplasia [ADH] and 15 benign breast disease). Immunohistochemical (IHC) data for MMP-1, HER2, ER/PR and P53 from these donors were also analyzed. IHC results for MMP-1 were scored as 0 (no expression) or increasing expression of+1, +2 or +3. Data were analyzed using Pearson's chi-square test to identify statistical significance.

Results: A significantly higher number of patients in the IBC group expressed high MMP-1 (+2 and +3; p &lt;0.001) while the benign group had the least number of patients expressing higher MMP-1 (score +3; p = 0.0075). In the IBC group, among patients with low levels of MMP-1 (+1), 57% had the 1G/1G phenotype, and among those expressing high levels of MMP-1 (+2 and +3), over 70% were 1G/2G heterozygotes or 2G/2G homozygotes. The 2G allele frequency in the ADH group was 0.62 and these patients had higher MMP-1 expression (+2 and +3). Further analyses of HER2, ER/PR and P53 in relation to the MMP-1 polymorphism within the IBC group showed MMP-1 allelic variation in Her-2 positive group was significantly different compared with Her-2 negative group (p = 0.039), with a distribution curve shifted to a greater frequency of 2G homozygosity. A similar result was also observed in P53 positive group when compared with P53 negative group (p = 0.043).

Conclusions: 1) In the IBC group, the 2G insertion polymorphism contributes to MMP-1 over expression. 2) Increased expression of MMP-1 in ADH and higher 2G allele frequency are consistent with the hypothesis that increased MMP-1 2G polymorphism plays a role in initiation of ADH through up regulation of MMP-1 expression. 3) Earlier studies show prognostic role for the coexistence of increased expression of HER2 and P53 in breast cancer. Our observation of a significant increase in the 2G homozygotes in HER2 and P53 positive patients supports a prognostic role for this polymorphism and suggests its possible association with other breast cancer markers. Thus, the MMP-1 2G polymorphism may both contribute to breast disease onset and serve as a prognostic marker for breast cancer.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-07-09.