RISK OF BONE METASTATIZATION IN BREAST CANCER:ROLE OF MATRIX METALLOPROTEINASES AND ADAMS TISSUE EXPRESSION

INTRODUCTION Breast cancer is the most common female neoplasm in developed countries: it represents the first cause of death for cancer in women between 40-55 years old. Bone metastasis are common in patients affected by advanced breast cancer. In patients affected by metastatic breast cancer (MBC), the bone represents the most common site of metastatization. Some elements can explain the high frequency of bone metastasis: the blood flow is abundant in the bone marrow, the cancer cells produce adhesion molecules than link stromal cells and bone matrix, the bone tissue is a source of growth factors. Bone metastasis from breast cancer are usually ostheolytic. The matrix metalloproteinases (MMPs) are able to degrade all ECM components; ADAMs functions include cellular adhesion, migration and signaling. Their principal substrates are transmembrane proteins as adhesion proteins and precursors of growth factors and cytokines. OBJECTIVES OF THE STUDY This mono institutional study evaluates the expression of a panel of biological and molecular markers (MMP, ADAMs and TIMPS) in two cohorts of patients with breast cancers affected or not affected by bone metastasis. The main end point is to verify if there is some marker significantly correlated with the risk of bone metastatization. PATIENTS AND METHODS 297 records of breast cancer patients operated between 1985 and 2001 at San Paolo Hospital in Milan were analyzed. All avaible slides were revised, stained with hematossilin and eosin, Tissue Microarray (TMA) was created with Tissue Arrayer Minicore instrument. RESULTS Mean age of the population is 61 years (standard deviation 11.7; range 27-89 years). The control group has 207 patients (69,7% of the total). The group with bone metastasis consists of 90 patients (31,3% of the total). Of those, 45 (50%) have only bone localization of disease while 50% have both visceral and bone metastasis. In the control group, 173 patients out of 206 (83,6%) had ductal invasive carcinoma, 25 patients (12,1%) had lobular invasive carcinoma while 9 patients (4,3%) had other hystotype. Tumoral grading, MMP1, ADAM 17 and ADAM 12 were the parameters selected by the univariate analysis. ADAM12 expression was the only parameter significantly different between the two groups (78,26% vs 91,11% with p 0.036, OR=2.59, 95%IC 1.06-6.29). DICUSSION Our study shows that ADAM 12 is the only hyper expressed protein in tumoral tissue that is significant related with bone matastatization. ADAM12 induces estrogen-resistance in hormone sensitive tumors, play a role as mediator of the resistance to the hormonal treatment. 73,3% had a ER-positive and ADAM12-positive disease. It can be hypothesized that some ormonosensitive patients, treated with hormones would develop bone metastatization due to hyperexpression of ADAM12. Targeting ADAM12, together with hormonal treatment, could be a new approach to overcome anti estrogenic resistance.