ABSTRACT
Although triple negative breast cancer (TNBC) is a small percentage of all breast cancers, to date, TNBC is one of the most challenging types of breast cancer for basic and clinic research because TNBC patients display a high risk of relapse, shorter overall survival and limited therapeutic options after completion of conventional chemotherapy compared with patients with other breast cancer subtypes. The epidermal growth factor receptor (EGFR) is a promising target for TNBC treatment. Although near infrared-photothermal therapy (NIR-PTT) using anti-EGFR antibody-conjugated gold nanorods (anti-EGFR-GNs), has attracted considerable interest for non-invasive and targeted TNBC treatment through an activation of apoptotic pathway, it is unclear whether anti-EGFR-GNs-combined NIR-PTT modulates the induction of autophagy contributing to cell death. Therefore, we investigated the autophagic cell death in cultured TNBC cells and mouse xenograft tumors during anti-EGFR-GNs-combined NIR-PTT. We here found that the cytotoxicity induced by anti-EGFR-GNs-combined NIR-PTT was rescued by treatment with autophagy inhibitor, 3-methyladenine (3-MA). Anti-EGFR-GNs-combined NIR-PTT induced remarkable levels of autophagy activity as evidenced by a large number of autophagic vesicles and a significant increase in autophagy-specific proteins; microtubule-associated protein light chain 3 (LC3), p62, beclin-1, and autophagy-related gene5 (Atg5), accompanying the inhibition of AKT-mTOR signaling pathway responsible for inducing autophagy. Moreover, in mouse xenograft tumors, anti-EGFR-GNs-combined NIR-PTT also increased LC3 and beclin-1 levels. Our findings, for the first time, demonstrate that anti-EGFR-GNs-combined NIR-PTT remarkably induces autophagy leading to EGFR-targeted cancer cell death.
Subject(s)
Antibodies/immunology , Autophagy/drug effects , ErbB Receptors/immunology , Gold/chemistry , Infrared Rays , Metal Nanoparticles/toxicity , Adenine/analogs & derivatives , Adenine/toxicity , Animals , Antibodies/chemistry , Autophagy/radiation effects , Autophagy-Related Protein 5/metabolism , Beclin-1/metabolism , Cell Line, Tumor , Female , Humans , Metal Nanoparticles/chemistry , Mice , Mice, Inbred BALB C , Mice, Nude , Microscopy, Electron, Transmission , Microscopy, Fluorescence , Microtubule-Associated Proteins/metabolism , Phototherapy , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/metabolism , Transplantation, Heterologous , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/therapyABSTRACT
BACKGROUND: We conducted a retrospective study to evaluate the local recurrence (LR) rate depending on the use of neoadjuvant chemotherapy (NCT) and to determine the oncologic safety of breast-conserving surgery (BCS) after NCT by comparing LR between patients treated with BCS and mastectomy in clinical stage III breast cancer patients. PATIENTS AND METHODS: Between 2004 and 2007, 166 patients underwent BCS or mastectomy after NCT (NCT group) and 193 patients underwent surgery first (surgery group) in clinical stage III breast cancer patients. Patients whose tumor size became ≤4 cm after NCT, 57 patients underwent mastectomy (mastectomy group) 39 patients underwent preplanned BCS (preplanned BCS group), and 33 patients underwent downstaged BCS (downstaged BCS group). The recurrence rates between the groups and risk factors for LR were analyzed. RESULTS: The 5-year LR-free survival rates were 93.6 % in the NCT group and 95.9 % in the surgery group (P = 0.108). In the NCT group, the 5-year LR-free survival rates were 96.3 % in the mastectomy group, 94.7 % in the preplanned BCS group and 90.9 % in the downstaged BCS group (P = 0.669). High expression of Ki-67 was a predictor of LR in patients in three groups (Hazard ratio 8.300, P = 0.049). CONCLUSIONS: Our findings suggest that BCS after NCT in clinical stage III patients is oncologically safe in terms of LR if breast tumor size is ≤4 cm after NCT and Ki-67 is a predictor of LR after NCT.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/pathology , Breast Neoplasms/therapy , Mastectomy, Segmental , Neoadjuvant Therapy , Neoplasm Recurrence, Local , Adult , Breast Neoplasms/metabolism , Chemotherapy, Adjuvant , Cyclophosphamide/administration & dosage , Disease-Free Survival , Docetaxel , Doxorubicin/administration & dosage , Female , Fluorouracil/administration & dosage , Humans , Ki-67 Antigen/metabolism , Lymphatic Metastasis , Methotrexate/administration & dosage , Middle Aged , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/therapy , Neoplasm Staging , Paclitaxel/administration & dosage , Radiotherapy, Adjuvant , Retrospective Studies , Risk Factors , Survival Rate , Taxoids/administration & dosageABSTRACT
BACKGROUND: Cancer stem cells (CSCs) are highly tumorigenic and are responsible for tumor progression and chemoresistance. Noninvasive imaging methods for the visualization of CSC populations within tumors in vivo will have a considerable impact on the development of new CSC-targeting therapeutics. METHODOLOGY/PRINCIPAL FINDINGS: In this study, human breast cancer stem cells (BCSCs) transduced with dual reporter genes (human ferritin heavy chain [FTH] and enhanced green fluorescence protein [EGFP]) were transplanted into NOD/SCID mice to allow noninvasive tracking of BCSC-derived populations. No changes in the properties of the BCSCs were observed due to ferritin overexpression. Magnetic resonance imaging (MRI) revealed significantly different signal intensities (R(2)* values) between BCSCs and FTH-BCSCs in vitro and in vivo. In addition, distinct populations of pixels with high R(2)* values were detected in docetaxel-treated FTH-BCSC tumors compared with control tumors, even before the tumor sizes changed. Histological analysis revealed that areas showing high R(2)* values in docetaxel-treated FTH-BCSC tumors by MRI contained EGFP+/FTH+ viable cell populations with high percentages of CD44+/CD24- cells. CONCLUSIONS/SIGNIFICANCE: These findings suggest that ferritin-based MRI, which provides high spatial resolution and tissue contrast, can be used as a reliable method to identify viable cell populations derived from BCSCs after chemotherapy and may serve as a new tool to monitor the efficacy of CSC-targeting therapies in vivo.