ABSTRACT
Melanoma differentiation associated gene-9 (MDA-9), Syntenin-1, or syndecan binding protein is a differentially regulated prometastatic gene with elevated expression in advanced stages of melanoma. MDA-9/Syntenin expression positively associates with advanced disease stage in multiple histologically distinct cancers and negatively correlates with patient survival and response to chemotherapy. MDA-9/Syntenin is a highly conserved PDZ-domain scaffold protein, robustly expressed in a spectrum of diverse cancer cell lines and clinical samples. PDZ domains interact with a number of proteins, many of which are critical regulators of signaling cascades in cancer. Knockdown of MDA-9/Syntenin decreases cancer cell metastasis, sensitizing these cells to radiation. Genetic silencing of MDA-9/Syntenin or treatment with a pharmacological inhibitor of the PDZ1 domain, PDZ1i, also activates the immune system to kill cancer cells. Additionally, suppression of MDA-9/Syntenin deregulates myeloid-derived suppressor cell differentiation via the STAT3/interleukin (IL)-1ß pathway, which concomitantly promotes activation of cytotoxic T lymphocytes. Biologically, PDZ1i treatment decreases metastatic nodule formation in the lungs, resulting in significantly fewer invasive cancer cells. In summary, our observations indicate that MDA-9/Syntenin provides a direct therapeutic target for mitigating aggressive breast cancer and a small-molecule inhibitor, PDZ1i, provides a promising reagent for inhibiting advanced breast cancer pathogenesis.
Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Interleukin-1beta/genetics , Lung Neoplasms/drug therapy , Oxadiazoles/pharmacology , Pyrimidines/pharmacology , Syntenins/genetics , Animals , Antineoplastic Agents/chemical synthesis , Breast Neoplasms/genetics , Breast Neoplasms/immunology , Breast Neoplasms/pathology , Cell Line, Tumor , Chemokine CCL11/genetics , Chemokine CCL11/immunology , Chemokine CCL17/genetics , Chemokine CCL17/immunology , Female , Gene Expression Regulation, Neoplastic , Humans , Interleukin-10/genetics , Interleukin-10/immunology , Interleukin-1alpha/genetics , Interleukin-1alpha/immunology , Interleukin-1beta/antagonists & inhibitors , Interleukin-1beta/immunology , Interleukin-23 Subunit p19/genetics , Interleukin-23 Subunit p19/immunology , Interleukin-5/genetics , Interleukin-5/immunology , Lung Neoplasms/genetics , Lung Neoplasms/immunology , Lung Neoplasms/secondary , Mice , Mice, Inbred BALB C , Oxadiazoles/chemical synthesis , Pyrimidines/chemical synthesis , Signal Transduction , Syntenins/antagonists & inhibitors , Syntenins/immunology , T-Lymphocytes, Cytotoxic/drug effects , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/pathology , Tumor Burden/drug effects , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: Reducing the rate of margin positivity and reoperations remains a paramount goal in breast-conserving surgery (BCS). This study assesses the effectiveness of standard partial mastectomy with cavity shave margins (CSM) compared with partial mastectomy with selective margin resection (SPM), with regard to outcomes of the initial surgeries, re-excisions, and overall costs. PATIENTS AND METHODS: This is a retrospective review of 122 eligible breast cancer patients who underwent BCS at one institution. The CSM and SPM groups each included 61 patients, matched for presurgical diagnoses and clinical stage. Data including margin status, rates and reason for re-excision, associated operation times, and costs were analyzed. RESULTS: Patients undergoing CSM had less than half the rate of positive margins (PMs) (10% vs. 23%; P = .03) and re-excisions (8% vs. 23%; P = .02) compared with SPM. In the former group, the margin involvement was focal, and re-excisions were performed almost exclusively for PMs. For SPM, the majority (92%) of PMs were on the main lumpectomy specimen rather than the selective margins, and re-excisions included, in addition to PMs, extensive or multifocal negative but close margins. Reduced breast tissue volumes were removed with CSM, particularly for patients undergoing a single surgery (47 vs. 165 cm3; P < .001). The initial surgery with CSM is on average 27% more costly than that for SPM (P < .001), due to the increased pathology costs which are partially offset by the increased re-excision rates in SPM. CONCLUSION: Circumferential cavity shaving, associated with consistent lower PMs, tissue volumes excised, and re-excision rates, is appropriate for routine implementation as a method offering superior surgical outcomes.
