How ADAM-9 and ADAM-11 Differentially From Estrogen Receptor Predict Response to Tamoxifen Treatment in Patients with Recurrent Breast Cancer: a Retrospective Study

Abstract

Purpose: To evaluate the predictive value of the disintegrin and metalloproteinases, ADAM-9, ADAM-10, ADAM-11, and ADAM-12, and of the matrix metalloproteinases, MMP-2 and MMP-9, in patients with recurrent breast cancer treated with tamoxifen. Experimental Design: A retrospective study was done on 259 frozen specimens of estrogen receptor^positive primary breast carcinomas from patients who developed recurrent disease and were treated with tamoxifen as the first line of therapy. The expression levels of the biological factors were assessed by real-time quantitative reverse transcriptase PCR. Results: Using log-transformed continuous variables, increasing levels of ADAM-9 [odds ratio (OR) = 1.41; P = 0.015] and decreasing levels of MMP-9 (OR, 0.81; P = 0.035) predicted favorable disease control independent from the traditional predictive factors. Furthermore, when tumors were dichotomized at the median level of 70% tumor cell nuclei, our univariate analysis showed particularly strong results for the group of 153 patients with primary tumors containing 30% or more stromal cells. Although estrogen receptor levels lost their predictive power for this group of patients, high levels of ADAM-9 (OR, 1.59; P = 0.007) and ADAM-11 (OR, 1.65; P = 0.001) were significantly associated with a higher efficacy of tamoxifen therapy. Conclusions: Our results show that especially for primary tumors containing stromal elements, the assessment of mRNA expression levels of ADAM-9 and ADAM-11could be useful to identify patients with recurrent breast cancer who are likely to benefit or fail from tamoxifen therapy.

Emerging roles of ADAM and ADAMTS metalloproteinases in cancer

“…Some ADAMs could be relevant markers of therapeutic response. ADAM-9 and ADAM-11 mRNA levels in tumours are indeed associated with better response to tamoxifen therapy and ADAM-9 protein production is an indicator of poor prognosis [147,148]. Patients displaying elevated levels of ADAMTS-8 and low levels of ADAMTS-15 have a general poor clinical outcome [149].…”

Selective recruitment of breast cancer anti-estrogen resistance genes and relevance for breast cancer progression and tamoxifen therapy response

“…Primary tumor tissue processing was done as described previously (Sieuwerts et al 2005). In summary, 20-60 cryostat sections of 30 mm, corresponding to 30-100 mg, were cut from frozen tissues for RNA isolation.…”

“…RNA isolation, cDNA synthesis, and quantification of mRNA and quality control checks were done as described in detail before (Sieuwerts et al 2005). RNA samples without distinct rRNA bands or failing to amplify efficiently with the housekeeper primer sets (see below) were excluded from this study.…”

“…Specific gene primer sets not meeting the stringent quality criteria (i.e. detection of genomic DNA or poor amplification efficiency) were excluded (Sieuwerts et al 2005). The primer sets were used in combination with SYBR green PCR Master Mix (Applied Biosystems) and are described in Supplementary Table S1, see section on supplementary data given at the end of this article.…”

“…Some gene quantifications were performed using inventoried TaqMan Gene Expression Assays from Applied Biosystems in combination with TaqMan Universal PCR Master Mix (Applied Biosystems) and in accordance with the protocol recommended by the manufacturer (Supplementary Table S1). ESR1 and PGR mRNA transcripts were measured as described before (Sieuwerts et al 2005(Sieuwerts et al , 2007. To enable comparison of the mRNA levels in different samples, values were normalized using the average expression levels of a set of housekeeping genes containing HMBS, HPRT1, and B2M.…”