ABSTRACT
Breast Cancer (BC) is a highly heterogeneous disease whose most aggressive behavior is displayed by triple-negative breast cancer (TNBC), which lacks an efficient targeted therapy. Despite its controversial role, one of the proteins that having been linked with BC is Annexin A1 (AnxA1), which is a Ca+2 binding protein that acts modulating the immune system, cell membrane organization and vesicular trafficking. In this work we analyzed tissue microarrays of BC samples and observed a higher expression of AnxA1 in TNBCs and in lymph node metastasis. We also observed a positive correlation in primary tumors between expression levels of AnxA1 and its receptor, FPR1. Despite displaying a lesser strength, this correlation also exists in BC lymph node metastasis. In agreement, we have found that AnxA1 was highly expressed and secreted in the TNBC cell line MDA-MB-231 that also expressed high levels of FPR1. Furthermore, we demonstrated, by using the specific FPR1 inhibitor Cyclosporin H (CsH) and the immunosuppressive drug Cyclosporin A (CsA), the existence of an autocrine signaling of AnxA1 through the FPR1. Such signaling, elicited by AnxA1 upon its secretion, increased the aggressiveness and survival of MDA-MB-231 cells. In this manner, we demonstrated that CsA works very efficiently as an FPR1 inhibitor. Finally, by using CsA, we demonstrated that FPR1 inhibition decreased MDA-MB-231 tumor growth and metastasis formation in nude mice. These results indicate that FPR1 inhibition could be a potential intervention strategy to manage TNBCs displaying the characteristics of MDA-MB-231 cells. FPR1 inhibition can be efficiently achieved by CsA.
Subject(s)
Annexin A1/metabolism , Cyclosporine/administration & dosage , Receptors, Formyl Peptide/metabolism , Triple Negative Breast Neoplasms/metabolism , Up-Regulation , Adult , Aged , Aged, 80 and over , Animals , Autocrine Communication/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclosporine/pharmacology , Female , Gene Expression Regulation, Neoplastic , Humans , Lymphatic Metastasis , Mice , Mice, Nude , Middle Aged , Triple Negative Breast Neoplasms/drug therapy , Up-Regulation/drug effects , Xenograft Model Antitumor AssaysABSTRACT
Circulating tumor cells are important markers of tumor progression and can reflect tumor behavior in metastatic colorectal cancer (mCRC). Identification of proteins that confer resistance to treatment is an important step to predict response and better selection of treatment for patients. Multidrug resistance-associated protein 1 (MRP1) and Multidrug resistance-associated protein 4 (MRP4) play a role in irinotecan-resistance, and Excision Repair Cross-Complementation group 1 (ERCC1) expression can confer resistance to platinum compounds. Here, we included 34 patients with mCRC and most of them received FOLFIRI or FOLFOX chemotherapy (91.1%). CTCs were isolated by ISET(®) Technology and identified in 30 patients (88.2%), with a median of 2.0 CTCs/mL (0-31.0). We analyzed the immunocytochemical expression of MRP1, MRP4 and ERCC1 only in patients who had previously detectable CTCs, accordingly to treatment received (n = 19, 15 and 13 patients, respectively). Among patients treated with irinotecan-based chemotherapy, 4 out of 19 cases with MRP1 positive CTCs showed a worse progression free survival (PFS) in comparison to those with MRP1 negative CTCs (2.1 months vs. 9.1 months; p = 0.003). None of the other proteins studied in CTCs had significant association with PFS. We analyzed also histological sections of primary tumors and metastases by immunohistochemistry, and found no association with clinicopathological characteristics or with PFS. Our results show MRP1 as a potential biomarker of resistance to treatment with irinotecan when found in CTCs from mCRC patients. This is a small proof-of-principle study and these early findings need to be validated in a larger cohort of patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Drug Resistance, Neoplasm/genetics , Gene Expression , Multidrug Resistance-Associated Proteins/genetics , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Female , Humans , Irinotecan , Male , Middle Aged , Multidrug Resistance-Associated Proteins/metabolism , Neoplasm Grading , Neoplasm Metastasis , Pilot Projects , Prognosis , Survival AnalysisABSTRACT
BACKGROUND: Thyroid nodules are the most common surgical disease of the thyroid. Fine-needle aspiration biopsy (FNAB) is the most commonly employed tool for establishing a diagnosis. However, 15% to 25% of FNAB reports yield inconclusive results. Immunostaining of cytological smears from FNAB with galectin-3 has been proposed as a tool for differentiating between benign and malignant nodules. We performed a systematic review to evaluate the utility of galectin-3. METHODS: Prospective studies of nodules with FNAB reports of "follicular neoplasm" and with a definitive diagnosis confirmed by histopathology were selected. Calculations of individual sensitivity, specificity, and positive and negative likelihood ratios were made. RESULTS: The articles selected were those with the best methodological quality. CONCLUSION: Galectin-3 could be a good tool to guide therapeutic decision in patients with thyroid nodules and FNAB results of follicular neoplasm, but available information has methodological flaws that precludes a definitive answer about galectin-3 utility in the clinical setting.
