Therapeutic evolution in HR+/HER2- breast cancer: from targeted therapy to endocrine therapy.

Breast cancer, a complex and varied disease, has four distinct subtypes based on estrogen receptor and human epidermal growth factor receptor 2 (HER2) levels, among which a significant subtype known as HR+/HER2-breast cancer that has spurred numerous research. The prevalence of breast cancer and breast cancer-related death are the most serious threats to women's health worldwide. Current progress in treatment strategies for HR+/HER2-breast cancer encompasses targeted therapy, endocrine therapy, genomic immunotherapy, and supplementing traditional methods like surgical resection and radiotherapy. This review article summarizes the current epidemiology of HR+/HER2-breast cancer, introduces the classification of HR+/HER2-breast cancer and the commonly used treatment methods. The mechanisms of action of various drugs, including targeted therapy drugs and endocrine hormone therapy drugs, and their potential synergistic effects are deeply discussed. In addition, clinical trials of these drugs that have been completed or are still in progress are included.

A Novel Prognostic Prediction Model Based on Pyroptosis-Related Clusters for Breast Cancer.

Breast cancer (BC) is the most common cancer affecting women and the leading cause of cancer-related deaths worldwide. Compelling evidence indicates that pyroptosis is inextricably involved in the development of cancer and may activate tumor-specific immunity and/or enhance the effectiveness of existing therapies. We constructed a novel prognostic prediction model for BC, based on pyroptosis-related clusters, according to RNA-seq and clinical data downloaded from TCGA. The proportions of tumor-infiltrating immune cells differed significantly in the two pyroptosis clusters, which were determined according to 38 pyroptosis-related genes, and the immune-related pathways were activated according to GO and KEGG enrichment analysis. A 56-gene signature, constructed using univariate and multivariate Cox regression, was significantly associated with progression-free interval (PFI), disease-specific survival (DSS), and overall survival (OS) of patients with BC. Cox analysis revealed that the signature was significantly associated with the PFI and DSS of patients with BC. The signature could efficiently distinguish high- and low-risk patients and exhibited high sensitivity and specificity when predicting the prognosis of patients using KM and ROC analysis. Combined with clinical risk, patients in both the gene and clinical low-risk subgroup who received adjuvant chemotherapy had a significantly lower incidence of the clinical event than those who did not. This study presents a novel 56-gene prognostic signature significantly associated with PFI, DSS, and OS in patients with BC, which, combined with the TNM stage, might be a potential therapeutic strategy for individualized clinical decision-making.

2­Hydroxypropyl­ß­cyclodextrin blocks autophagy flux and triggers caspase­8­mediated apoptotic cascades in HepG2 cells.

The cyclodextrin derivative, 2­Hydroxypropyl-ß­cyclodextrin (HPßCD), from the cyclodextrin family is widely used as a drug carrier and offers promising strategies for treating neurodegenerative diseases and atherosclerosis regression. However, its side effects are not fully understood. Therefore, the aim of the present study was to investigate the possible adverse effects of relatively high concentrations of HPßCD on hepatocytes. It was found that a high dose (20 mM) of HPßCD treatment significantly inhibited the AKT/mTOR pathway and disrupted infusion of autophagosomes and lysosomes, which rapidly led to massive autophagosome accumulation in HepG2 cells. The autophagosomal membrane serves as a platform for caspase­8 oligomerization, which is considered as the key step for its self­activation. Using flow cytometry and TUNEL assay, increased apoptosis of HepG2 cells treated with a high dose HPßCD (20 mM) for 48 h was observed. In addition, western blotting results demonstrated that the expression of cleaved­caspase­8 was positively associated with microtubule­associated protein 1 light chain 3 BII expression, which is an indicator of autophagosome level in the cytoplasm. Therefore, the present study provided novel evidence that HPßCD might be a potential risk contributing to the pathophysiological process of hepatic diseases, especially in an autophagy­deficient state.

Berberine ameliorates blockade of autophagic flux in the liver by regulating cholesterol metabolism and inhibiting COX2-prostaglandin synthesis.

Excessive cholesterol contributes to the development of cardiovascular diseases. Berberine (BBR) has been reported to regulate cholesterol homeostasis. Here, we found that BBR could ameliorate the hepatic autophagic flux blockade caused by cholesterol overloading. The underlying mechanism included lowering hepatic cholesterol level, modulating the cholesterol distribution targeting the plasma membrane by decreasing sterol carrier protein 2 expression and inhibiting cyclooxygenase 2-mediated production of prostaglandin metabolites, which decreased the phosphorylation of Akt/mTOR. Our study provides evidences that BBR could be a therapeutic agent for protecting liver under cholesterol overloading via the regulation of autophagic flux.

Exposure to 2,4-dichlorophenoxyacetic acid induced PPARß-dependent disruption of glucose metabolism in HepG2 cells.

2,4-Dichlorophenoxyacetic acid is one of the most widely used herbicides. Its impact on health is increasingly attracting great attentions. This study aimed to investigate the effect of 2,4-dichlorophenoxyacetic acid on glucose metabolism in HepG2 cells and the underlying mechanism. After 24 h exposure to 2,4-dichlorophenoxyacetic acid, glycogen was measured by PAS staining and glucose by ELISA in HepG2 cells. The expression of genes involved in glucose metabolism was measured by real-time PCR, Western blotting, and immunofluorescence. HepG2 cells presented more extracellular glucose consumption and glycogen content after exposed to 2,4-dichlorophenoxyacetic acid. Expression of gluconeogenesis-related genes, FoxO1, and CREB is significantly elevated. Moreover, PPARß was up-regulated dose-dependently. SiRNA knockdown of PPARß completely rescued the increase of glycogen accumulation and glucose uptake, and the up-regulation of FOXO1 and CREB expression. Our findings propose novel mechanisms that 2,4-dichlorophenoxyacetic acid causes glucose metabolism dysfunction through PPARß in HepG2 cells.

Organochloride pesticides modulated gut microbiota and influenced bile acid metabolism in mice.

Organochlorine pesticides (OCPs) can persistently accumulate in body and threaten human health. Bile acids and intestinal microbial metabolism have emerged as important signaling molecules in the host. However, knowledge on which intestinal microbiota and bile acids are modified by OCPs remains unclear. In this study, adult male C57BL/6 mice were exposed to p, p'-dichlorodiphenyldichloroethylene (p, p'-DDE) and ß-hexachlorocyclohexane (ß-HCH) for 8 weeks. The relative abundance and composition of various bacterial species were analyzed by 16S rRNA gene sequencing. Bile acid composition was analyzed by metabolomic analysis using UPLC-MS. The expression of genes involved in hepatic and enteric bile acids metabolism was measured by real-time PCR. Expression of genes in bile acids synthesis and transportation were measured in HepG2 cells incubated with p, p'-DDE and ß-HCH. Our findings showed OCPs changed relative abundance and composition of intestinal microbiota, especially in enhanced Lactobacillus with bile salt hydrolase (BSH) activity. OCPs affected bile acid composition, enhanced hydrophobicity, decreased expression of genes on bile acid reabsorption in the terminal ileum and compensatory increased expression of genes on synthesis of bile acids in the liver. We demonstrated that chronic exposure of OCPs could impair intestinal microbiota; as a result, hepatic and enteric bile acid profiles and metabolism were influenced. The findings in this study draw our attention to the hazards of chronic OCPs exposure in modulating bile acid metabolism that might cause metabolic disorders and their potential to cause related diseases in human.

Organochloride pesticides induced hepatic ABCG5/G8 expression and lipogenesis in Chinese patients with gallstone disease.

BACKGROUND: Organochlorine pesticides (OCPs) are one kind of persistent organic pollutants. Although they are reported to be associated with metabolic disorders, the underlying mechanism is unclear. We explored the association of OCPs with gallstone disease and its influence on hepatic lipid metabolism. MATERIALS AND METHODS: OCPs levels in omentum adipose tissues from patients with and without gallstone disease between 2008 and 2011 were measured by GC-MS. Differences of gene expression involved in hepatic lipid metabolism and hepatic lipids content were compared in liver biopsies between groups with high and low level of OCPs. Using HepG2 cell lines, the influence on hepatic lipid metabolism by individual OCP was evaluated in vitro. RESULTS: In all patients who were from non-occupational population, there were high levels of ß-hexachlorocyclohexane (ß-HCH) and p',p'-dichloroethylene (p',p'-DDE) accumulated in adipose tissues. Both ß-HCH and p', p'-DDE levels were significantly higher in adipose tissues from patients with gallstone disease (294.3± 313.5 and 2222± 2279 ng/g of lipid) than gallstone-free controls (282.7± 449.0 and 2025±2664 ng/g of lipid, P< 0.01) and they were strongly related with gallstone disease (P for trend = 0.0004 and 0.0138). Furthermore, higher OCPs in adipose tissue led to increase in the expression of hepatic cholesterol transporters ABCG5 and G8 (+34% and +27%, P< 0.01) and higher cholesterol saturation index in gallbladder bile, and induced hepatic fatty acids synthesis, which was further confirmed in HepG2 cells. CONCLUSIONS: OCPs might enhance hepatic secretion of cholesterol into bile via ABCG5/G8 which promoting gallstone disease as well as lipogenesis.