Mammographic density and matrix metalloproteinases in breast tissue

Abstract

Mammographic density is a strong risk factor for breast cancer, yet the underlying histopathologic correlates are not clear. Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) play important roles in multiple stages of tumorigenesis. This study examined the association between mammographic density and expression of MMPs 1, 3, 9, and 12 and TIMP3 in benign and malignant breast tissue of 277 women with mainly Caucasian and Japanese ancestry. Tissue microarrays with up to 4 benign and 4 malignant cores per woman were stained immunohistochemically and evaluated. Digitized prediagnostic mammograms were assessed for densities using a computer-assisted method. General linear models adjusted for known confounders were applied to estimate mean densities by staining category. Strong expression of all MMPs was about twice as frequent in malignant as in benign tissue, while TIMP3 expression in stromal tissue was higher in benign than malignant cores. For MMP3 and 9, less than 10% of cores stained positive; thus, they were not further analyzed. None of the markers showed a statistically significant association with breast density in the entire study population and ethnic-specific results were conflicting and difficult to explain. Although not statistically significant, mean density was consistently lower with more extensive TIMP3 expression in stromal and epithelial tissue. These findings indicate that the higher breast cancer risk in women with dense breasts may be influenced by lower TIMP3 expression. However, future investigations into activities and ratios of additional proteases and their inhibitors as well as other pathways, such as inflammation, are needed.

Fig. 1

Examples of stromal and epithelial staining in tissue microarray. Representative immunohistochemical staining on breast tissue microarray. a–c Epithelial staining; a no stain, b weak stain, c strong stain. d-e Stromal staining; d no stain, e any stain

Fig. 2

Percent density for MMP1, MMP12, and TIMP3 by tissue type and ethnicity (Adjusted for age at mammogram, BMI, ethnicity, parity, age at first live birth, age at menarche, menopausal status, hormone use at mammogram, family history of breast cancer, and tumor stage)