Minghua Ji

Exosomes from Drug-Resistant Breast Cancer Cells Transmit Chemoresistance by a Horizontal Transfer of MicroRNAs

Adriamycin and docetaxel are two agents commonly used in treatment of breast cancer, but their efficacy is often limited by the emergence of chemoresistance. Recent studies indicate that exosomes act as vehicles for exchange of genetic cargo between heterogeneous populations of tumor cells, engendering a transmitted drug resistance for cancer development and progression. However, the specific contribution of breast cancer-derived exosomes is poorly understood. Here we reinforced others report that human breast cancer cell line MCF-7/S could acquire increased survival potential from its resistant variants MCF-7/Adr and MCF-7/Doc. Additionally, exosomes of the latter, A/exo and D/exo, significantly modulated the cell cycle distribution and drug-induced apoptosis with respect to S/exo. Exosomes pre-treated with RNase were unable to regulate cell cycle and apoptosis resistance, suggesting an RNA-dependent manner. Microarray and polymerase chain reaction for the miRNA expression profiles of A/exo, D/exo, and S/exo demonstrated that they loaded selective miRNA patterns. Following A/exo and D/exo transfer to recipient MCF-7/S, the same miRNAs were significantly increased in acquired cells. Target gene prediction and pathway analysis showed the involvement of miR-100, miR-222, and miR-30a in pathways implicated in cancer pathogenesis, membrane vesiculation and therapy failure. Furthermore, D/exo co-culture assays and miRNA mimics transfection experiments indicated that miR-222-rich D/exo could alter target gene expression in MCF-7/S. Our results suggest that drug-resistant breast cancer cells may spread resistance capacity to sensitive ones by releasing exosomes and that such effects could be partly attributed to the intercellular transfer of specific miRNAs.

Expression of the PXR gene in various types of cancer and drug resistance

Pregnane X receptor (PXR) is a member of the nuclear receptor superfamily of ligand-regulated transcription factors. PXR is a key xenobiotic receptor that regulates the expression of genes implicated in drug metabolism, detoxification and clearance, including drug metabolizing enzymes and transporters, suggesting that it is significant in the drug resistance of cancer cells. PXR is expressed in a wide range of tissues in the human body. Studies have demonstrated that PXR is expressed in a variety of tumor types, correlating not only with drug resistance but also with the cell proliferation, apoptosis and prognosis of cancer. The purpose of the present review is to provide a comprehensive review of PXR and its potential roles in multidrug resistance and the biological characteristics of PXR-positive tumors.

MicroRNAs delivered by extracellular vesicles: an emerging resistance mechanism for breast cancer

Resistance to chemotherapy and endocrine therapy as well as targeted drugs is a major problem in treatment of breast cancer. Over the last decades, emerging studies have revealed that extracellular vesicles, which are chronically released by breast cancer cells and surrounding stromal cells, influence the action of most commonly used therapeutics. Such modulatory effects have been related to the transport of biologically active molecules including proteins and functional microRNAs. In this review, we highlight recent studies regarding extracellular vesicle-mediated microRNA delivery in formatting drug resistance. We also suggest the use of extracellular vesicles as a promising method in antiresistance treatment.

Polymorphisms in genes involved in drug detoxification and clinical outcomes of anthracycline-based neoadjuvant chemotherapy in Chinese Han breast cancer patients

Background: The large individual variability for anticancer drugs in both outcome and toxicity risk makes the identification of pharmacogenetic markers that can be used to screen patients before therapy selection an attractive prospect. Aims: This work aimed to evaluate the importance of genetic polymorphisms involved in drug detoxification to predict clinical outcomes of anthracycline-based neoadjuvant chemotherapy for breast cancer. Results: GSTP1 313 AA genotype was associated with a poor clinical response relative to G allele carrier (58.4% vs 80.8%; p = 0.006), and MDR1 3435 TT genotype had a worse response compared with C allele carrier (33.3% vs 71.2% p = 0.001). Patients with both the adverse genotypes of GSTP1 314AA and MDR 3435TT showed the worst therapy efficacy in all (14.3%; p = 0.000). Kaplan-Meier survival analysis showed that the patients with no adverse genotype were associated with decreased hazard of relapse (p = 0.002), compared with those with 1 or 2 adverse genotypes. Multivariate analysis demonstrated that clinical response and no adverse genotype was independent predictors of disease-free survival (DFS). Methods: Genotyping was performed by allele-specific oligonucleotide ligation reaction (MnSOD, CAT, GSTP1), multiplex PCR (GSTM1, GSTT1) or PCR-RFLP (MDR1). Based on 153 patients received anthracycline-based neoadjuvant chemotherapy, these genotypes or their combinations in relation to treatment-related response, hematologic toxicity and DFS were investigated. Conclusions: These results suggest that polymorphisms in GSTP1 and MDR1 may help to predict clinical response and DFS of anthracycline-based chemotherapy, and a polygenic pathway approach should provide more useful information. The findings required independent prospective confirmation.

Joint detection of multiple immunohistochemical indices and clinical significance in breast cancer

Breast cancer is one of the most common malignancies in women. This study was conducted to analyze the association between the expressions of eight immunohistochemical (IHC) indices and clinicopathological characteristics in breast cancers (BCs) and investigate the clinical significance. IHC Envision ldpe-g-nvp was used to detect the expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER2), vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), p53, type II topoisomerase (TOPO II) and Ki-67 in postoperative paraffin blocks of 286 cases of invasive BC and statistically analyzed their correlations with clinicopathological characteristics. The positive rates of ER, PR, HER2, VEGF, p53, EGFR, TOPO II and Ki-67 expression were 62.24, 41.96, 57.34, 53.85, 81.82, 46.85, 54.55 and 69.93%, respectively. ER expression was negatively correlated with age, tumor size and histological grade (P<0.05) and PR expression was negatively correlated with age and histological grade (P<0.05). Among the ER, PR and c-erbB-2 statuses, a significant correlation was observed between ER expression and PR status (P=0.0000), whereas the expression of ER and PR exhibited a negative correlation with HER2 status (P<0.05). We also demonstrated a significant correlation between EGFR expression and lymph node metastasis (P=0.0240), p53 expression and tumor size (P=0.0300), p53 and Ki-67 expression and histological grade (P<0.05) and the expressions of VEGF, EGFR, p53, TOPO II, Ki-67 and HER2 status (P<0.05). In addition, the Luminal B and HER2/neu subtypes exhibited a close correlation with age (P<0.01), while the HER2/neu and triple-negative subtypes were positively correlated with poor histological grade (P<0.05). In conclusion, there is a definite correlation between IHC indices and clinicopathological characteristics in BCs. Combined detection of these indices may be significant in the evaluation of biological behavior and prognosis of BC and thus in the diagnosis and comprehensive treatment of this disease.

Improved ataxia telangiectasia mutated kinase inhibitor KU60019 provides a promising treatment strategy for non-invasive breast cancer

It has previously been reported that KU60019, as a highly effective radiosensitizer, inhibits the DNA damage response and blocks radiation-induced phosphorylation of key ataxia telangiectasia mutated targets in human glioma cells. The present study investigated whether KU60019 affects cell physiological activities and strengthens the efficacy of doxorubicin-induced DNA damage. It was demonstrated that the compound suppressed the proliferation of MCF-7 cells and significantly increased chemosensitization. In addition, KU60019 (without doxorubicin) inhibited MCF-7 cell motility and invasion, potentially by acting on the phosphorylated-Akt and E-cadherin signaling pathways. Although the majority of MCF-7 cells were arrested at the G1/S phase following treatment with KU60019, the combination of the two compounds did not result in such a marked effect on the cell cycle. In conclusion, KU60019 is a potent chemosensitizer in combination with doxorubicin, therefore, it may provide a promising strategy for non-invasive breast cancer.

Huntingtin-associated protein 1: A potential biomarker of breast cancer

It is reported that patients with Huntingtons disease (HD) have a low incidence of cancer. In this study, we investigated the expression of huntingtin-associated protein 1 (HAP1), the ligand of HDs production, in breast tumor and normal tissues. We found that HAP1 expression was significantly lower in tumor compared to normal tissues. We then transfected the HAP1 gene into the breast cancer lines MCF-7 and MDA-MB-231, and results showed that the overexpression of HAP1 reduced the growth of the two cell lines. In addition, we observed that HAP1 also reduced invasion and migration, and upregulated apoptosis in MCF-7 cells; however, these changes were not observed in MDA-MB-231 cells. We also demonstrated that the expression of EGFR and apoptosis-related genes might be involved in cell proliferation and apoptosis. In conclusion, overexpression of HAP1 reduced in vitro cell growth in breast cancer cell lines, suppressed the migration and invasion, and promoted the apoptosis of certain cell lines. Therefore, HAP1 is a potential molecular target for the diagnosis and treatment of breast cancer.

Inflammatory myofibroblastic tumor of the breast coexisting with breast cancer: a case report.

Background: The inflammatory myofibroblastic tumor (IMT) is an uncommon low-risk lesion with only a few cases described in the literature. Case Report: Here, we report a unique case of an IMT coexisting with breast cancer. Modified radical mastectomy was performed, followed by TAC chemotherapy (taxotere, adriamycin and cyclophosphamide). At the 2-year follow-up, the patient continues to be disease free. Conclusion: At the preoperative stage, definitive diagnoses of masses are extremely difficult; surgery is advised only after the diagnosis is confirmed by pathological examination.