New insights in the interaction of FGF/FGFR and steroid receptor signaling in breast cancer

Luminal breast cancer (BrCa) has a favorable prognosis compared to other tumor subtypes. However, with time tumors may evolve and lead to disease progression. Thus, there is a great interest in unraveling the mechanisms that drive tumor metastasis and endocrine resistance. In this review we focused in one of the many pathways that have been involved in tumor progression, the FGF/FGFR axis. We emphasized in data obtained from in vivo experimental models since we believe that in luminal BrCa, tumor growth relies in a crosstalk with the stromal tissue. We revisited the studies that illustrate the interaction between hormone receptors and FGFR. We also highlighted the most frequent alterations found in BrCa cell lines and we provide a short review on the trials that use FGFR inhibitors in combination with endocrine therapies. The analysis of this data suggests that there are many players involved in this pathway that might be also targeted to decrease FGF signaling in addition to specific FGFR inhibitors that may be exploited to increase their efficacy.

Network pharmacology study of Citrus reticulata and Pinellia ternata in the treatment of non-small cell lung cancer

It has been recognized that Citrus reticulata and Pinellia ternata have a good therapeutic effect on NSCLC. However, the potential mechanism of C. reticulata and P. ternata in the treatment of NSCLC based on network pharmacology analysis is not clear. The “Drug-Component-Target-Disease” network was constructed by Cytoscape, and the protein interaction (PPI) network was constructed by STRING. Our study indicated that 18 active ingredients of C. reticulata and P. Ternata were screened from the TCMSP database, and 56 target genes of C. reticulata and P. Ternata for the treatment of NSCLC were identified, and we constructed the “Drug-Component-Target-Disease” network. In this study, we screened 56 PPI core genes to establish a PPI network. We concluded that the network pharmacology mechanism of the effect of C. reticulata and P. Ternata on NSCLC may be closely related to the protein expressed by TP53, ESR1, FOS, NCOA3 and MAPK8, and these may play the therapeutic roles by regulating the IL-17 signaling pathway, antigen processing and presentation, microRNAs in cancer and endocrine resistance.

Effect of Eucommia ulmoides leaves on hyperuricemia and kidney injury induced by a high-fat/high-fructose diet in rats

Eucommia ulmoides leaves have unique advantages in the treatment of metabolic diseases. In this study, network pharmacology and molecular-docking methods were used to predict the effects and action mechanisms of the major components of E. ulmoides leaves on hyperuricemia. Combining literature collection, we used SciFinder and the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform to collect E. ulmoides leaf flavonoid and iridoid components. Swiss Target Prediction, SEA, GeneCards, and the OMIM database were used to obtain core targets, and the STRING protein database was performed as core targets for gene ontology enrichment Set and KEGG analyses. Molecular docking was applied to predict the pathways regulating the metabolism of uric acid. The selected targets and targeting efficacy were validated using a rat model of hyperuricemia and renal injury induced by a high-fat and high-fructose diet. A total of 32 chemical components with effective targets, which regulated the PI3K-AKT pathway and endocrine resistance, were collected. Isoquercetin, kaempferol, and quercetin were predicted via network pharmacology to have potential bioactivities and strong docking binding forces. Molecular docking results showed that iridoids and flavonoids are bound to proteins related to inflammation and uric acid metabolism. In addition, it was verified via animal experiments that an E. ulmoides leaf extract ameliorated hyperuricemia, renal injury, and inflammation, which are closely related to the targets IL-6, TNF-α, TLR4, and GLUT9. In conclusion, E. ulmoides leaf flavonoids and iridoids ameliorate hyperuricemia and uric-acid–induced inflammation through a multi-component, multi-target, and multi-pathway mechanism, which provides a theoretical basis for the development of therapeutics from E. ulmoides leaf components.

A Novel Group of Genes that Causes Endocrine Resistance in Breast Cancer Identified by Dynamic Gene Expression Analysis

Breast cancer (BC) is the most common type of cancer and the second leading cancer-related cause of death in women worldwide. Endocrine therapy is an effective therapeutic approach for estrogen receptor (ER)-positive breast cancer; however, in many cases, tumor regrowth occurs after the therapy and the tumor becomes unresponsive anymore. While some gene mutations contribute to the resistance in some patients, the underlying causes of the resistance to endocrine therapies are mostly undetermined. In this study, we utilized our recently developed statistical approach to investigate the dynamic behavior of gene expression during the development of endocrine resistance and identified a novel group of genes that can be crucial to the development of resistance in BC. The expression of these genes is not only altered in cell models during the endocrine resistance development but also significantly changed in endocrine-resistant patients. Surprisingly, this group of genes was also identified as a group of key candidate genes in triple-negative breast cancer (TNBC), suggesting that endocrine resistance and TNBC share the same mechanisms during their development. Our findings explain some of the genetic underlying reasons for endocrine resistance and provide the potential to develop novel common therapeutic approaches against endocrine-resistant BC and TNBC.

Overview of PROTACs targeting the estrogen receptor: Achievements for biological and drug discovery

: Estrogen receptors (ERs) are steroid hormone receptors, which belong to a large nuclear receptor family. Endocrine diseases correlate strongly with dysregulated ER signaling. Traditional therapies continue to rely on small molecule inhibitors, including aromatase inhibitors (AIs) and selective estrogen receptor modulators (SERMs), all of which permit acquired resistance to endocrine therapy. Proteolytic targeting chimeras (PROTACs) offer unprecedented potential for solving acquired endocrine resistance. ARV-471, an ER-targeting PROTAC developed by Arvinas, entered clinical trials in 2019 to treat patients suffering from locally advanced or metastatic ER-positive/HER2-negative breast cancer and has since been approved by the US FDA. In this review, we will focus on progress in developing ER-targeting PROTACs from publications and patents aimed at the treatment of endocrine diseases.

ARID1A Mutation in Metastatic Breast Cancer: A Potential Therapeutic Target

Distant metastasis is the principal cause of mortality for breast cancer patients. Targeting specific mutations that have been acquired during the evolution process of advanced breast cancer is a potential means of enhancing the clinical efficacy of treatment strategies. In metastatic breast cancer, ARID1A is the most prevalent mutation of the SWI/SNF complex, which regulates DNA repair, recombination, and gene transcription. The low expression of ARID1A is associated with poor disease-free survival and overall survival of patients with luminal A or HER2-rich breast cancer. In addition, ARID1A plays a prominent role in maintaining luminal characteristics and has an advantage for identifying responses to treatment, including endocrine therapies, HDAC inhibitors and CDK4/6 inhibitors. The therapeutic vulnerabilities initiated by ARID1A alterations encourage us to explore new approaches to cope with ARID1A mutant-related drug resistance or metastasis. In this review, we describe the mutation profiles of ARID1A in metastatic breast cancer and the structure and function of ARID1A and the SWI/SNF complex as well as discuss the potential mechanisms of ARID1A-mediated endocrine resistance and therapeutic potential.

An immune-humanized patient-derived xenograft model of estrogen-independent, hormone receptor positive metastatic breast cancer

Background Metastatic breast cancer (MBC) is incurable, with a 5-year survival rate of 28%. In the USA, more than 42,000 patients die from MBC every year. The most common type of breast cancer is estrogen receptor-positive (ER+), and more patients die from ER+ breast cancer than from any other subtype. ER+ tumors can be successfully treated with hormone therapy, but many tumors acquire endocrine resistance, at which point treatment options are limited. There is an urgent need for model systems that better represent human ER+ MBC in vivo, where tumors can metastasize. Patient-derived xenografts (PDX) made from MBC spontaneously metastasize, but the immunodeficient host is a caveat, given the known role of the immune system in tumor progression and response to therapy. Thus, we attempted to develop an immune-humanized PDX model of ER+ MBC. Methods NSG-SGM3 mice were immune-humanized with CD34+ hematopoietic stem cells, followed by engraftment of human ER+ endocrine resistant MBC tumor fragments. Strategies for exogenous estrogen supplementation were compared, and immune-humanization in blood, bone marrow, spleen, and tumors was assessed by flow cytometry and tissue immunostaining. Characterization of the new model includes assessment of the human tumor microenvironment performed by immunostaining. Results We describe the development of an immune-humanized PDX model of estrogen-independent endocrine resistant ER+ MBC. Importantly, our model harbors a naturally occurring ESR1 mutation, and immune-humanization recapitulates the lymphocyte-excluded and myeloid-rich tumor microenvironment of human ER+ breast tumors. Conclusion This model sets the stage for development of other clinically relevant models of human breast cancer and should allow future studies on mechanisms of endocrine resistance and tumor-immune interactions in an immune-humanized in vivo setting.