Efficacy and safety of PD-1 and PD-L1 inhibitors combined with chemotherapy in randomized clinical trials among triple-negative breast cancer.

Background: The combination of immune checkpoint inhibitors (ICIs) and chemotherapy (CT) is a new strategy to explore cancer treatment in recent years, and it is also practiced in triple-negative breast cancer (TNBC). However, several published randomized controlled trials (RCTs) reported heterogeneous results. We conducted this meta-analysis to yield insights into the efficacy and safety of the combination of ICIs and CT for TNBC patients in both the adjuvant and neoadjuvant settings. Method: EMBASE, PUBMED, Cochrane, and www.clinicaltrials.gov databases were searched to determine potential eligible studies from the inception to 20 May 2022. Published RCTs on PD-1/PD-L1 ICIs combined with CT for TNBC patients were included. Result: This meta-analysis included six double-blind RCTs comprising 4,081 TNBC patients treated with PD-1 or PD-L1 ICIs plus CT or placebo plus CT. The combination strategy benefited a better pathologic complete response (pCR) by 29% (RR = 1.29; 95% CI: 1.17-1.41; I2 = 0%) and a better progression-free survival (PFS) (HR = 0.82; 95% CI: 0.74-0.90; I2 = 0%) in the neoadjuvant and the adjuvant settings, respectively, especially in PD-L1-positive population (HR = 0.71; 95% CI: 0.62-0.81; I2 = 13%). The safety profiles were generally tolerable in both settings but the combination treatment will increase the risk of severe adverse events in the adjuvant setting (RR = 1.33; 95% CI 1.08-1.62, I2 = 0%). Additionally, the combination will increase the risk of any-grade hypothyroidism, hyperthyroidism, pneumonia, and rash in the adjuvant setting, and the risk of any-grade hypothyroidism, hyperthyroidism, infusion-related reactions, and severe cutaneous reactions in the neoadjuvant setting. Conclusion: This meta-analysis demonstrated a significant pCR benefit and confirms the PFS benefit with PD-1/PD-L1 ICIs plus CT in TNBC patients with tolerable safety events in both neoadjuvant and adjuvant settings.

PD-1/PD-L1 Inhibitor-Associated Myocarditis: Epidemiology, Characteristics, Diagnosis, Treatment, and Potential Mechanism.

Immune checkpoint inhibitors (ICIs) induce T-cell activation against cancer cells, and due to their anti-tumor function in multiple cancers, ICIs have been considered an important option for oncotherapy. PD-1/PD-L1 inhibitors are now widely used as ICIs for many types of cancers in clinical practices. Myocarditis induced by anti-PD-1/PD-L1 agents is uncommon but shows potentially fatal toxicity. In this review, we attempted to conclude the incidence, characteristics, diagnosis, and treatments, as well as illustrate the potential pathogenesis from the perspectives of T-lymphocyte infiltration, disturbance of regulatory T cells, cytokines, macrophage-mediated inflammatory response, and synergistic effect of PD-1/PD-L1 and CTLA4.

Metastasis to Breast from Extramammary Solid Tumors and Lymphomas: A 20-Year Population-Based Study.

To discuss the clinicopathological features and prognosis of metastases to the breast from extramammary solid tumors and lymphomas, we reviewed Cancer Hospital of Chinese Academy of Medical Sciences database from 01/01/2000 to 12/31/2020. Fifty-nine patients were identified. The most common primary sites for breast metastases were lymph node and pulmonary, followed by nasal cavity, ovary, skin, etc. All the patients were treated with chemotherapy, 18 were operated, 14 accepted radiotherapy. Metastasis to breast should be considered in any patient with tumor history presenting a breast lump. Pathological with immunohistochemical examination should be performed to identify the original site.

Primary Giant Cell Tumor of the Breast With Pulmonary Metastasis: A Case Report and Review of the Literature.

Giant cell tumor of soft tissue (GCT-ST) is an extremely rare tumor that is similar in morphology and immunohistochemistry to giant cell tumor of the bone. Almost 80% of these tumors occur in the upper and lower extremities, and the breast is a very rare location. Here, we report a case of a 65-year-old female patient with a small mobile palpable lump in the left breast. Although the left breast tumor was considered malignant on preoperative imaging, no evidence of malignant tumor was found by ultrasound-guided core needle biopsy (CNB). Subsequently, the left breast tumor was confirmed as a malignant tumor by intraoperative rapid pathological examination. The initial treatment of the tumor was wide local excision and sentinel lymph node biopsy, and it was confirmed to be GCT-ST by histopathology and immunohistochemistry. Despite surgical treatment achieving clear surgical margins, the patient experienced lung metastases within a year of her initial treatment. Fortunately, the patient underwent surgical treatment of lung metastases, and at the last follow-up, the patient was still alive. This is the first case of a primary soft tissue tumor of the breast that has undergone surgical intervention after lung metastasis. This case report highlights the complexity of the clinical diagnosis and treatment of GCT-ST arising from the breast. Surgery may be another good treatment when the patient develops lung metastases.

Efficacy and Safety of Anti-PD-1/ PD-L1 Monotherapy for Metastatic Breast Cancer: Clinical Evidence.

Background: Success has been reported in PD-1/PD-L1 blockade via pembrolizumab, atezolizumab, or avelumab monotherapy in manifold malignancies including metastatic breast cancer. Due to lack of large-scale study, here we present interim analyses to evaluate the safety and efficacy of these promising strategies in patients with advanced breast cancer. Methods: Six studies including 586 advanced breast cancer patients treated with anti-PD-1/PD-L1 monotherapy agents before July 1, 2020, were included. The anti-PD-1/PD-L1 agents include pembrolizumab, atezolizumab, land avelumab. Statistics was analyzed by R software and IBM SPSS Statistics 22. Results: Global analysis showed that for this monotherapy, the complete response was 1.26%, partial response was 7.65%, objective response rate (ORR) was 9.85%, and disease control rate (DCR) was 18.33%. 1-year overall survival rate and 6-month progression-free survival rate were 43.34 and 17.24%. Overall incidence of adverse events (AEs) was 64.18% in any grade and 12.94% in severe grade, while the incidence of immune-related AEs (irAEs) was approximately 14.75%: the most common treatment-related AEs of any grade that occurred in at least 5% of patients were arthralgia and asthenia; the most common severe treatment-related AEs occurred in at least 1% of patients were anemia and autoimmune hepatitis; the most common irAEs were hypothyroidism. Besides, the incidence of discontinue and death due to treatment-related AEs was about 3.06 and 0.31%, respectively. Additionally, by comparing efficacy indicators between PD-L1-positive and PD-L1-negative groups, an implicated correspondence between efficacy and the expression of PD-L1 biomarker was found: the PR was 9.93 vs 2.69%; the ORR was 10.62 vs. 3.07%; the DCR was 17.95 vs. 4.71%. Conclusion: Anti-PD-1/PD-L1 monotherapy showed a manageable safety profile and had a promising and durable anti-tumor efficacy in metastatic breast cancer patients. Higher PD-L1 expression may be closely correlated to a better clinical efficacy.

Molecular and Clinical Characterization of LAG3 in Breast Cancer Through 2994 Samples.

Despite the promising impact of cancer immunotherapy targeting CTLA4 and PD1/PDL1, numerous cancer patients fail to respond. LAG3 (Lymphocyte Activating 3), also named CD233, serves as an alternative inhibitory receptor to be targeted in the clinic. The impacts of LAG3 on immune cell populations and coregulation of immune responses in breast cancer remain largely unknown. To characterize the role of LAG3 in breast cancer, we investigated transcriptome data and associated clinical information derived from 2,994 breast cancer patients. We estimated the landscape of the relationship between LAG3 and 10 types of cell populations of breast cancer. We investigated the correlation pattern between LAG3 and immune modulators in pancancer, particularly the synergistic role of LAG3 with other immune checkpoint members in breast cancer. LAG3 expression was closely related to the malignancy of breast cancer and may serve as a potential biomarker. LAG3 may play an important role in regulating the tumor immune microenvironment of T cells and other immune cells. More important, LAG3 may synergize with CTLA4, PD1/PDL1, and other immune checkpoints, thereby contributing more evidence to improve combination cancer immunotherapy by simultaneously targeting LAG3, PD1/PDL1, and CTLA4.

Molecular and Clinical Characterization of CCT2 Expression and Prognosis via Large-Scale Transcriptome Profile of Breast Cancer.

Molecular chaperones play important roles in regulating various cellular processes and malignant transformation. Expression of some subunits of molecular chaperone CCT/TRiC complex have been reported to be correlated with cancer development and patient survival. However, little is known about the expression and prognostic significance of Chaperonin Containing TCP1 Subunit 2 (CCT2). CCT2 is a gene encoding a molecular chaperone that is a member of the chaperonin containing TCP1 complex (CCT), also known as the TCP1 ring complex (TRiC). Through the Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) databases, we systematically reviewed a total of 2,994 cases with transcriptome data and analyzed the functional annotation of CCT2 by Gene ontology and KEGG analysis. Univariate and multivariate survival analysis were performed to investigate the prognostic value of CCT2 in breast cancer. We found CCT2 was significantly upregulated in various tumors. In breast cancer, CCT2 expression was significantly upregulated in HER2-positive (HER2+) group, and more malignant group. In addition, we investigated correlations between CCT2 and other CCT members. Interestingly, almost all CCTs expression were positively correlated with each other, but not CCT6B. Survival analysis suggested that CCT2 overexpression was independently associated with worse prognosis of patients with breast cancer, especially in luminal A subtype. In summary, our results revealed that CCT2 might be involved in regulating cell cycle pathway, and independently predicted worse prognosis in breast cancer patients. These findings may expand understanding of potential anti-CCT2 treatments. To our knowledge, this is the largest and most comprehensive study characterizing the expression pattern of CCT2 together with its prognostic values in breast cancer.

Epidemiological and clinical characteristics of cancer patients with COVID-19: A systematic review and meta-analysis of global data.

There are minimal data regarding the prevalence of cancer in patients with coronavirus disease 2019 (COVID-19), as well as the incidence of severe illness and rate of mortality in COVID-19 patients with cancer. PubMed, Embase, Cochrane Library, and Web of Science were systematically searched, from database inception to July 15, 2020, for studies of patients with COVID-19 that included information regarding comorbid cancer. In total, 109 eligible global studies were included in this systematic review. Ninety studies with 94,845 COVID-19 patients, among which 4106 exhibited comorbid cancer, were included in the meta-analysis regarding prevalence of comorbid cancer. Twenty-three studies with 71,969 COVID-19 patients, among which 4351 with comorbid cancer had severe illness or death, were included in the meta-analysis. The overall prevalence of cancer among COVID-19 patients was 0.07 (95% CI 0.05-0.09). The cancer prevalence in COVID-19 patients was higher in Europe (0.22, 95% CI 0.17-0.28) than in the Asia-Pacific region (0.04, 95% CI 0.03-0.06) or North America (0.05, 95% CI 0.04-0.06). The cancer prevalence in COVID-19 patients aged >60 years was 0.10 (95% CI 0.07-0.14), while the prevalence among patients aged ≤60 years was 0.05 (95% CI 0.03-0.06). The pooled prevalence of severe illness among COVID-19 patients with cancer was 0.34 (95% CI 0.26-0.42) and the pooled mortality rate of COVID-19 patients with cancer was 0.20 (95% CI 0.16-0.25). Pooled incidences of severe illness among COVID-19 patients with cancer from Asia Pacific, Europe, and North America were 0.38 (95% CI 0.24-0.52), 0.39 (95% CI 0.25-0.53), and 0.26 (95% CI 0.20-0.31), respectively; pooled mortality rates from the Asia-Pacific region, Europe, and North America were 0.17 (95% CI 0.10-0.24), 0.26 (95% CI 0.18-0.35), and 0.19 (95% CI 0.13-0.25), respectively.

Nutritional Risk Index Predicts Survival in Patients With Breast Cancer Treated With Neoadjuvant Chemotherapy.

Nutritional risk index (NRI) is an index based on ideal body weight that aims to present body weight and serum albumin levels. It has been utilized to discriminate patients at risk of postoperative complications and predict the postoperative outcome of major surgeries. However, this index remains limited for breast cancer patients treated with neoadjuvant chemotherapy (NACT). The research explores the clinical and prognostic significance of NRI in breast cancer patients. This study included 785 breast cancer patients (477 cases received NACT and 308 cases did not) were enrolled in this retrospective study. The optimal NRI cutoff value was evaluated by receiver operating characteristic (ROC) curve, then reclassified as low NRI group (<112) and high NRI group (≥112). The results demonstrated that NRI independently predicted survival on disease-free survival (DFS) and overall survival (OS) by univariate and multivariate Cox regression survival analyses [P = 0.019, hazard ratio (HR): 1.521, 95% CI: 1.071-2.161 and P = 0.004, HR: 1.415, 95% CI: 1.119-1.789; and P = 0.026, HR:1.500, 95% CI: 1.051-2.143 and P < 0.001, HR: 1.547, 95% CI: 1.221-1.959]. According to the optimal cutoff value of NRI, the high NRI value patients had longer mean DFS and OS time in contrast to those with low NRI value patients (63.47 vs. 40.50 months; 71.50 vs. 56.39 months). Furthermore, the results demonstrated that the high NRI score patients had significantly longer mean DFS and OS time than those with low NRI score patients in early-stage breast cancer (χ2 = 9.0510, P = 0.0026 and χ2 = 9.2140, P = 0.0024) and advanced breast cancer (χ2 = 6.2500, P = 0.0124 and χ2 = 5.8880, P = 0.0152). The mean DFS and OS values in patients with high NRI scores were significantly longer in contrast to those with low NRI scores in different molecular subtypes. The common toxicities after NACT were hematologic and gastrointestinal reactions, and the NRI had no statistically significant effects on toxicities, except in nausea (χ2 = 9.2413, P = 0.0024), mouth ulcers (χ2 = 4.8133, P = 0.0282), anemia (χ2 = 8.5441, P = 0.0140), and leukopenia (χ2 = 11.0951, P = 0.0039). NRI serves as a minimally invasive, easily accessible and convenient prognostic tool for evaluating breast cancer prognoses and treatment efficacy, and may help doctors in terms of selecting measures of greater efficiency or appropriateness to better treat breast cancer.

JAK2 expression is correlated with the molecular and clinical features of breast cancer as a favorable prognostic factor.

Janus kinases are a family of non-receptor tyrosine kinases involved in autoimmune diseases and malignancies. In breast cancer, the immune related role of JAK2 remains unclear. We aimed to investigate its role at transcriptome level and its relationship with the clinical outcome of breast cancer. This study enrolled a total of 2994 breast cancer samples with transcriptome data, including 1090 samples from The Cancer Genome Atlas (TCGA) and 1904 from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC). JAK2 expression was significantly upregulated in both PR positive group (P < 0.01) and HER2 negative group (P < 0.01), and was correlated with American Joint Committee on Cancer (AJCC) stage and tumor malignancies of breast cancer. Functional enrichment analysis revealed that genes correlated with JAK2 were mainly involved in essential functions associated with immune response. Intriguingly, we investigated the association between JAK2 and immune modulators in pan-cancer, JAK2 expression was positively correlated with most of these immune modulators. In clinical aspect, higher expression of JAK2 was an independent indicator of favorable prognosis in breast cancer patients. The expression of JAK2 is tightly related to the pathology and molecular pathology of breast cancer, and synergistic with other checkpoint members thereby playing a specific role in regulating tumor immune microenvironment. To our knowledge, this is the largest and most comprehensive study characterizing the expression pattern of JAK2 and its special immune functions together with its prognostic values in breast cancer. These findings might shed novel sights for future research in cancer immunotherapy by targeting immune checkpoint molecules.

Coordinated regulation of anthranilate metabolism and bacterial virulence by the GntR family regulator MpaR in Pseudomonas aeruginosa.

The GntR family regulators are widely distributed in bacteria and play critical roles in metabolic processes and bacterial pathogenicity. In this study, we describe a GntR family protein encoded by PA4132 that we named MpaR (MvfR-mediated PQS and anthranilate regulator) for its regulation of Pseudomonas quinolone signal (PQS) production and anthranilate metabolism in Pseudomonas aeruginosa. The deletion of mpaR increased biofilm formation and reduced pyocyanin production. RNA sequencing analysis revealed that the mRNA levels of antABC encoding enzymes for the synthesis of catechol from anthranilate, a precursor of the PQS, were most affected by mpaR deletion. Data showed that MpaR directly activates the expression of mvfR, a master regulator of pqs system, and subsequently promotes PQS production. Accordingly, deletion of mpaR activates the expression of antABC genes, and thus, increases catechol production. We also demonstrated that MpaR represses the rhl quorum-sensing (QS) system, which has been shown to control antABC activity. These results suggested that MpaR function is integrated into the QS regulatory network. Moreover, mutation of mpaR promotes bacterial survival in a mouse model of acute pneumonia infection. Collectively, this study identified a novel regulator of pqs system, which coordinately controls anthranilate metabolism and bacterial virulence in P. aeruginosa.

A Novel Prognostic Signature of mRNA-lncRNA in Breast Cancer.

Comprehensive genomic testing will be required to identify appropriate targets for the precision therapy of breast cancer. Although RNA sequencing (RNA-seq) is an unparalleled platform for this purpose, existing molecular-based prognostic signatures are not optimal for RNA-seq data. In this study, we analyzed RNA-seq datasets to generate a novel prognostic gene signature for breast cancer patients. RNA-seq and clinical datasets from breast cancer patients were obtained from The Cancer Genome Atlas and randomly assigned to training (n = 379) and test (n = 378) cohorts. Using the training cohort, sequential univariate Cox analysis, robust likelihood-based survival analysis, and stepwise multivariable Cox analysis identified a five-gene signature composed of one long noncoding RNA gene and four protein-coding genes. The five-gene signature was then used to dichotomize patients into risk groups and validated using Kaplan-Meier and multivariable Cox analyses. In the full test cohort, the high-risk group had worse overall survival (hazard ratio [HR] = 4.74, 95% confidence interval [CI] = 2.33-9.64, p < 0.0001) and worse relapse-free survival (HR = 2.26, 95% CI = 1.11-4.61, p = 0.024) than the low-risk group. Similarly, overall survival was worse in the high-risk group within nearly all clinically important subsets, including early stage disease (I/II) (HR = 7.87, 95% CI = 3.69-16.77, p < 0.0001), and luminal A (HR = 4.23, 95% CI = 1.11-16.12, p = 0.034), luminal B (HR = 12.79, 95% CI = 2.74-59.69, p = 0.001), and basal (HR = 18.11, 95% CI = 3.21-102.05, p = 0.001) subtypes. Notably, the five-gene signature exhibited superior prognostic performance compared with the Oncotype DX 21-gene signature. This novel five-gene signature may therefore be a powerful prognostic tool for personalized treatment of breast cancer patients as part of an integrated RNA-seq clinical sequencing program.

Research Progress Concerning Dual Blockade of Lymphocyte-Activation Gene 3 and Programmed Death-1/Programmed Death-1 Ligand-1 Blockade in Cancer Immunotherapy: Preclinical and Clinical Evidence of This Potentially More Effective Immunotherapy Strategy.

Although various immunotherapies have exerted promising effects on cancer treatment, many patients with cancer continue to exhibit poor responses. Because of its negative regulatory effects on T cells and its biological functions related to immune and inflammatory responses, there has been considerable emphasis on a protein-coding gene named lymphocyte-activation gene 3 (LAG3). Recently, evidence demonstrated marked synergy in its targeted therapy with programmed death-1 and programmed death-1 ligand-1 (PD-1/PD-L1) blockade, and a variety of LAG3 targeted agents are in clinical trials, indicating the important role of LAG3 in immunotherapy. This mini-review discusses preclinical and clinical studies investigating PD-1 pathway blockade in combination with LAG3 inhibition as a potentially more effective immunotherapy strategy for further development in the clinic. This strategy might provide a new approach for the design of more effective and precise cancer immune checkpoint therapies.

Mechanism of trastuzumab resistance caused by HER-2 mutation in breast carcinomas.

Background: Trastuzumab is an effective drug for the treatment of Her2-positive breast cancer. But, primary or secondary resistances to trastuzumab have become an important factor influencing the curative effect. The mechanisms of trastuzumab resistance are somewhat complex. The present work aims to explore the mechanism of trastuzumab resistance caused by HER-2 mutation in breast carcinomas. Methods: Firstly, the HER2 wild type (WT) and HER2 mutant (HER2 Q429R, HER2 Q429H and HER2 T798M are the commonest 3 types of mutations) MCF7 cell lines were established. Cell proliferation inhibition was then assessed by the Cell Counting Kit-8 assay and BrdU assay. Transwell invasion assays were also conducted to investigate the metastatic potential influenced by the HER2 mutation. Furthermore, Western blotting and co-immunoprecipitation were conducted to detect protein levels and the physical interaction of HER2 and trastuzumab. Results: The results showed that the mutant MCF7 cells were less sensitive to trastuzumab than the WTMCF7 cells. The mutation of HER2 almost had no influence on the expression of HER2 and the interaction of HER2 and trastuzumab. Finally, the mutation of HER2 weakened the inhibition of trastuzumab in the PI3K/AKT pathways. In addition, the inhibition of PI3K/AKT signaling-pathway increased the trastuzumab-sensitivity of HER2-mutant MCF7 cells. Conclusions: Dysregulation of the PI3K-AKT signaling-pathway was a key mechanism inducing the trastuzumab-resistance to HER2 mutant breast cancer cells.

LINC01355 suppresses breast cancer growth through FOXO3-mediated transcriptional repression of CCND1.

Previously, several protein-coding tumor suppressors localized at 1p36 have been reported. In the present work, we focus on functional long non-coding RNAs (lncRNAs) embedded in this locus. Small interfering RNA was used to identify lncRNA candidates with growth-suppressive activities in breast cancer. The mechanism involved was also explored. LINC01355 were downregulated in breast cancer cells relative to non-malignant breast epithelial cells. Overexpression of LINC01355 significantly inhibited proliferation, colony formation, and tumorigenesis of breast cancer cells. LINC01355 arrested breast cancer cells at the G0/G1 phase by repressing CCND1. Moreover, LINC01355 interacted with and stabilized FOXO3 protein, leading to transcriptional repression of CCND1. Importantly, LINC01355-mediated suppression of breast cancer growth was reversed by knockdown of FOXO3 or overexpression of CCND1. Clinically, LINC01355 was downregulated in breast cancer specimens and correlated with more aggressive features. There was a negative correlation between LINC01355 and CCND1 expression in breast cancer samples. LINC01355 acts as a tumor suppressor in breast cancer, which is ascribed to enhancement of FOXO3-mediated transcriptional repression of CCND1. Re-expression of LINC01355 may provide a potential therapeutic strategy to block breast cancer growth and progression.

Expression signatures and roles of microRNAs in inflammatory breast cancer.

Inflammatory breast cancer (IBC) is an infrequent but aggressive manifestation of breast cancer, which accounts for 2-4% of all breast cancer cases but responsible for 7-10% of breast cancer-related deaths, and with a 20-30% 10-year overall survival compared with 80% for patients with non-IBC with an unordinary phenotype, whose molecular mechanisms are still largely unknown to date. Discovering and identifying novel bio-markers responsible for diagnosis and therapeutic targets is a pressing need. MicroRNAs are a class of small non-coding RNAs that are capable to post-transcriptionally regulate gene expression of genes by targeting mRNAs, exerting vital and tremendous affects in numerous malignancy-related biological processes, including cell apoptosis, metabolism, proliferation and differentiation. In this study, we review present and high-quality evidences regarding the potential applications of inflammatory breast cancer associated microRNAs for diagnosis and prognosis of this lethal disease.

Immunological therapy: A novel thriving area for triple-negative breast cancer treatment.

Triple-negative breast cancer (TNBC) refers to cancers that are low in expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC tends to behave more aggressively than other types of breast cancer. Unlike other breast cancer subtypes (ie, ER-positive, HER2-positive subtypes), there are no approved targeted treatments available, other than the administration of chemotherapy. Immunotherapy is a new kind of treatment approach for TNBC when compared with the surgical treatment, chemotherapy, endocrine therapy, and molecular targeting therapy. The present article reviews the research progresses of immunotherapy for TNBC in recent years. The full text structure covers molecular classification of TNBC, active immunotherapy of TNBC, passive immunotherapy of TNBC, oncolytic immunotherapy and the prospect of immunotherapy for TNBC.

Ginsenoside Rg1 reverses stress-induced depression-like behaviours and brain-derived neurotrophic factor expression within the prefrontal cortex.

Depression is a major neuropsychiatric disorder that exerts deleterious effects upon public health. However, the neuronal mechanisms of depression remain largely uncharacterized, which has retarded the identification and development of effective therapeutic tools for the treatment of this disorder. The aim of this study was to explore the neuronal mechanisms underlying the protective effects of ginsenoside Rg1, a natural steroidal saponin found in ginseng, against chronic stress-induced depression.The results showed that chronic administration of ginsenoside Rg1 (40 mg/kg, i.p., 5 weeks) significantly ameliorated depression-like behaviours in rats as assessed in the sucrose preference and forced swim tests. Furthermore, chronic stress decreased the phosphorylation levels of the extracellular signal-regulated kinase and cAMP-response element-binding protein in the prefrontal cortex as well as producing a reduction of brain-derived neurotrophic factor expression. Of particular importance, all reductions in these parameters were significantly reversed by pre-treatment with ginsenoside Rg1. Taken together, the results of the present study suggest that the antidepressant-like effect of ginsenoside Rg1 might be mediated, at least in part, by activating the cAMP-response element-binding protein-brain-derived neurotrophic factor system within the prefrontal cortex. These findings not only reveal some of the underlying neuronal mechanisms of depression, but also the therapeutic potential of ginsenoside Rg1 as a preventive agent in the treatment of depression.