ABSTRACT
This study aims to explore the effects of the phosphatase and tension homolog (PTEN) expression level on autophagic status and on the resistance of breast cancer to trastuzumab treatment. PTEN and LC3I/II were knocked down with shRNA expression vectors, which were transfected into estrogen receptor (ER)-positive breast cancer cell lines. After trastuzumab treatment, the changes in the autophagy signal transduction pathways and autophagic proteins (LC3I/II, p62, LAMP, and cathepsin B) in these stably transfected cells were detected using western blot. The cells were also orthotopically implanted into nude mice to explore the influence of PTEN knockdown on tumor size, cell viability, and autophagic proteins after trastuzumab treatment. Similar determinations were performed using the LC3I/II overexpressed shPTEN breast cancer cells (LC3I/II-shPTEN). Downregulation of PTEN and autophagic proteins LC3-I and LC3-II was observed in resistant human breast cancer samples. Knockdown of PTEN and PTEN+ LC3I/II with shRNA in breast cancer cells resulted in increased resistance to trastuzumab. Consistently, trastuzumab treatment could not effectively reduce tumor size. Significant decreases in the levels of autophagic proteins LC3I/II, LAMP, p62, cathepsin B, and PI3K-Akt-mTOR and the signaling pathway protein Akt were found in PTEN knockdown cells, compared to the PTEN normal group, after trastuzumab administration, both in vitro and in vivo. However, these findings were reversed with the LC3I/II-shPTEN treatment. Therefore, the loss of PTEN may promote the development of primary resistance to trastuzumab in breast cancer via autophagy defects.
Subject(s)
Autophagy/drug effects , Breast Neoplasms/drug therapy , Microtubule-Associated Proteins/biosynthesis , PTEN Phosphohydrolase/genetics , Animals , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Mice , Microtubule-Associated Proteins/genetics , RNA-Binding Proteins/biosynthesis , Receptor, ErbB-2/genetics , Signal Transduction , TOR Serine-Threonine Kinases/biosynthesis , Trastuzumab/administration & dosage , Xenograft Model Antitumor AssaysABSTRACT
<p><b>OBJECTIVE</b>To assess the efficacy and safety of neoadjuvant 3-weekly paclitaxel plus trastuzumab (TH) in Chinese women with Her-2 overexpressing operable breast cancer.</p><p><b>METHODS</b>This is a single center open-label phase II clinical trial. The included patients underwent 4 cycles of neoadjuvant 3-weekly TH before surgery. The primary endpoint was pathologic complete response rate (pCR rate) and the secondary endpoint was overall response rate (OR rate). Patients were also stratified according to hormone receptor status, and pCR rate and OR rate were compared between subgroups. Adverse events were graded according to CTCAE v3.0.</p><p><b>RESULTS</b>There were 40 eligible patients entering this study with median age of 49 years. All patients completed 4 cycles of neoadjuvant treatment. pCR rate was 52.5% and OR rate was 87.5%. The differences of pCR and OR rates between subgroups were of no statistical significance. No cardiac toxicity event severer than grade 2 was recorded.</p><p><b>CONCLUSION</b>3-weekly TH regimen has satisfactory pCR rate and OR rate in Chinese patients with Her-2 overexpressing operable breast cancer and reliable safety.</p>
Subject(s)
Adult , Female , Humans , Middle Aged , Antibodies, Monoclonal , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols , Therapeutic Uses , Asian People , Breast Neoplasms , Drug Therapy , Metabolism , Pathology , Carcinoma, Ductal, Breast , Drug Therapy , Metabolism , Pathology , Lymphatic Metastasis , Neoadjuvant Therapy , Neutropenia , Paclitaxel , Receptor, ErbB-2 , Metabolism , Remission Induction , TrastuzumabABSTRACT
<p><b>OBJECTIVE</b>To evaluate the efficacy and safety of neoadjuvant chemotherapy combined with trastuzumab for HER2 positive breast cancers.</p><p><b>METHODS</b>PubMed online database, ASCO abstract database, SABCS abstract database, ESMO abstract database and CBMdisc database were searched for literatures related to trastuzumab in neoadjuvant chemotherapy for breast cancers. A meta-analysis was performed for retrieved literatures meeting the inclusion criteria.</p><p><b>RESULTS</b>Three clinical trials were included. Meta-analysis showed that compared to chemotherapy only, regimens combined with trastuzumab could significantly improved the pCR rate of HER2-positive breast cancers (RR=1.65, 95% CI 1.28-2.13, P<0.0001) without increasing the frequencies of cardiac toxicity (RR=1.16, 95% CI 0.82-1.64, P=0.41).</p><p><b>CONCLUSION</b>In neoadjuvant chemotherapy for HER2-positive breast cancers, chemotherapy combined with trastuzumab is superior to exclusive chemotherapy.</p>
