Matrix Metalloproteinase Genes Are Associated with Breast Cancer Risk and Survival: The Breast Cancer Health Disparities Study

Abstract

Matrix metalloproteinases (MMPs) contribute to cancer through their involvement in cancer invasion and metastasis. We evaluated genetic variation in MMP1 (9 SNPs), MMP2 (8 SNPs), MMP3 (4 SNPs), and MMP9 (3 SNPs) and breast cancer risk among Hispanic (2111 cases, 2597 controls) and non-Hispanic white (NHW) (1481 cases, 1586 controls) women in the Breast Cancer Health Disparities Study. Ancestral informative markers (n = 104) were assessed to determine Native American (NA) ancestry. MMP1 [4 single nucleotide polymorphisms (SNPs)] and MMP2 (2 SNPs) were associated with breast cancer overall. MMP1 rs996999 had strongest associations among women with the most NA ancestry (OR 1.61,95% CI 1.09,2.40) as did MMP3 rs650108 (OR 1.36, 95% CI 1.05,1.75) and MMP9 rs3787268 (OR 1.52, 95% CI 1.09,2.13). The adaptive rank truncated product (ARTP) showed a significant pathway partp value of 0.04, with a stronger association among women with the most NA ancestry (partp = 0.02). Significant pathway genes using the ARTP were MMP1 for all women (partp = 0.02) and MMP9 for women with the most NA ancestry (partp = 0.024); MMP2 was borderline significant overall (partp = 0.06) and MMP1 and MMP3 were borderline significant for women with the most NA ancestry (partp = 0.07 and 0.06 respectively). MMP1 and MMP2 were associated with ER+/PR+ and ER+/PR-tumors; MMP3 and MMP9 were associated with ER−/PR− tumors. The pathway was highly significant with survival (partp = 0.0041) with MMP2 having the strongest gene association (partp = 0.0007). Our findings suggest that genetic variation in MMP genes influence breast cancer development and survival in this genetically admixed population.

The extracellular matrix in breast cancer predicts prognosis through composition, splicing, and crosslinking

“…Despite their separation by the BM, stroma communicates with epithelia, and stromal changes are observed even in the early stages of malignancy [42]. Stromal ECM plays a major role in tumorigenesis: genetic work from both animal models [8,43] and the clinic [44,45] show that stromal gene expression can alter probablility of developing breast cancer. Importantly, gene expression patterns of normal stroma adjacent to breast cancers shows a different gene expression pattern from normal tissue from unaffected patients [46].…”

Matrix Metalloproteinase-9 -1562T Allele and its Combination with MMP-2 -735 C Allele are Risk Factors for Breast Cancer

“…The influence of MMP-9 C-1562T variants in the risk of breast cancer, its prognosis and metastasis has been investigated in various populations with controversial results (Grieu et al, 2004;Przybylowska et al, 2006;Hughes et al, 2007;Lei et al, 2007;McColgan et al, 2009;Beeghly-Fadiel et al, 2011;Zhou et al, 2011;Slattery et al, 2013;Chiranjeevi et al, 2014). The MMP-2 gene locates on chromosome 16 at q13-21 and has thirteen exons (Saeed et al, 2013).…”

Worse prognosis in breast cancer patients can be predicted by immunohistochemical analysis of positive MMP-2 and negative estrogen and progesterone receptors

“…These authors also suggest that the MMP-2 gene is an important pathway for tumor progression and invasiveness in ER+/PR+ and ER+/PR-samples. 12 Although based on a smaller sample, our study shows that ER-positive patients did not express MMP-2, while MMP-2-positive patients are ER-negative. A lack of MMP-2 could possibly become an important factor in certain subgroups of breast carcinoma while selecting the adjuvant therapy.…”

“…MMP-2 is a protein associated with metastasis and is extensively studied in several cancers. [11][12][13][14][15][16] ER and MMP-2 have shown a molecular relationship with E2 or estradiol binding in the E domains of ER, present in the plasma membrane. This interaction could activate MMP-2 and MMP-9 with subsequent transactivation of EGFR.…”

“…A loss of control of MMPs can result in pathological processes including inflammation, angiogenesis, cellular proliferation 11,12 and are directly involved in the metastatic tumor cell invasion process. 9 Among them, gelatinase A (MMP-2) is associated with a malignant phenotype, as it is responsible for the degradation of collagen fibers around tumors, thereby releasing these cells from the microenvironment in which they are established.…”