Search

Purpose of Review: Update on the most recent clinical evidence on selective estrogen receptor degraders (SERDs) in the treatment of hormone receptor (HR)-positive (HR +), human epidermal growth factor receptor 2 (HER2)-negative (HER2-) breast cancer. Recent Findings: Despite effective endocrine therapies, resistance commonly develops during treatment of HR + breast cancer and mutations in ESR1 account for a large proportion of resistance mechanisms. After demonstration of the superior efficacy of fulvestrant in ESR1-mutated tumors, recent advances allowed the development of a novel class of orally bioavailable selective estrogen receptor degraders (SERDs), which are beginning to revolutionize the field. The first approved oral SERD, elacestrant, is currently used in the second-line treatment of HR + /HER2- metastatic breast cancer, and a number of other oral SERDs are undergoing clinical evaluation in both the metastatic and early-stage settings. Summary: SERDs are a rapidly developing class of antiestrogens that show activity in treatment of tumors harboring ESR1 mutations associated with resistance to earlier generations of endocrine therapy, but knowledge gaps remain, and further research is necessary to better define their optimal use. [ABSTRACT FROM AUTHOR]

Background: In spite of the significant escalation in the depth of our conception and regulation of breast cancer over the past decades, the malady is still a serious community health challenge globally and poses a substantial tasks. Selective estrogen modulators (SERMs) such as Tamoxifen are approved for the therapy of this illness but developed drug resistance and unwanted side effects such as endometrial cancer caused by the long-term Tamoxifen chemotherapy limit their therapeutic applicability. Hence, developing new ER+ drugs with better therapeutic effect is strongly needed. In an attempt to overcome this challenge, this research is aimed at designing novel chromen-2-one analogues with better inhibition capacity against MCF-7 breast cancer cell line via structural modification of the reference compound and predict their activities using a developed QSAR model. Results: Four models were developed, and the first was selected for the design as it has the highest statistical parameters such as: coefficient of determination (R2 = 0.950), cross-validation coefficient (Qcv2 = 0.912), adjusted R2 (Radj2 = 0.935), and external validation R2 (Rpred2 = 0.7485). Twelve (12) new novel chromen-2-one analogs were designed through structural modification of the reference compound. Their activities was predicted using the selected model, and their pIC50 was found to be better than that of the reference compound and standard drug (Tamoxifen) used in the research. Results of pharmacokinetic study of the designed compounds revealed that they possess drug-likeness properties as none of them violated the Lipinski's rule of five while ADMET studies confirmed designed compounds 6, 8, 11 and 12 as orally safe and non-toxic. Furthermore, molecular docking analysis was performed between these orally safe designed compounds and the active site of the ER+ receptor and the result showed that they have higher binding affinities than the reference compound and the standard drug used for this research. Conclusion: Hence, designed compounds 6, 8, 11 and 12 can be used as novel ER+ breast cancer drug candidates after performing in vivo and in vitro studies. [ABSTRACT FROM AUTHOR]

As the essential sexual hormone, estrogen and its receptor has been proved to participate in the regulation of autoimmunity diseases and anti-tumor immunity. The adjustment of tumor immunity is related to the interaction between cancer cells, immune cells and tumor microenvironment, all of which is considered as the potential target in estrogen-induced immune system regulation. However, the specific mechanism of estrogen-induced immunity is poorly understood. Typically, estrogen causes the nuclear localization of estrogen/estrogen receptor complex and alternates the transcription pattern of target genes, leading to the reprogramming of tumor cells and differentiation of immune cells. However, the estrogen-induced non-canonical signal pathway activation is also crucial to the rapid function of estrogen, such as NF-κB, MAPK-ERK, and β-catenin pathway activation, which has not been totally illuminated. So, the investigation of estrogen modulatory mechanisms in these two manners is vital for the tumor immunity and can provide the potential for endocrine hormone targeted cancer immunotherapy. Here, this review summarized the estrogen-induced canonical and non-canonical signal transduction pathway and aimed to focus on the relationship among estrogen and cancer immunity as well as immune-related tumor microenvironment regulation. Results from these preclinical researches elucidated that the estrogen-target therapy has the application prospect of cancer immunotherapy, which requires the further translational research of these treatment strategies. [ABSTRACT FROM AUTHOR]

Estrogen receptor positive breast neoplasias represent over 70% of diagnosed breast cancers. Depending on the stage at which the tumor is detected, HER2 status and genomic risk, endocrine therapy is combined with either radio, chemo and/or targeted therapy. A growing amount of evidence supports the notion that components of the tumor microenvironment play specific roles in response to treatment and that strategies targeting these key interactions with tumor cells could pave the way to a new generation of therapies. In this review, we analyze the evidence suggesting different components of the tumor microenvironment play a role in hormone receptor positive breast cancer progression. In particular we focus on the immune system, carcinoma associated fibroblasts and the extracellular matrix. Further insight into the cross talk between these constituents of the microenvironment and the tumor cells may lead to therapies that eliminate disseminated metastatic cells early on, and thus reduce distant disease relapse which is the leading cause of death for patients who are diagnosed with this illness. [ABSTRACT FROM AUTHOR]

Endometriosis is a multifactorial disease in which genetic and environmental factors interact causing its pathogenesis. The aim of this study was to investigate the expression pattern of estrogen receptor α (ERα) and β (ERβ) in endometriosis patients compared to normal endometrioum (n=18) as a control by using Quantitative Real Time PCR method. Moreover, we also measured serum estradiol levels of endometriosis patients in the proliferation phase of the menstrual cycle using the enzyme-linked immunosorbent assay method. The mRNA expression of ERβ was significantly higher in the endometriosis group compared to control, and the result of t-test showed that were significantly different (P<0.05). Overexpression of ERβ in endometriosis was likely to have other significant important impacts in the pathology of endometriosis that allowed ERβ to stimulate prostaglandin production in endometriosis tissue and cells. Estradiol content did not correlate with the ERα expression, and it is weakly correlated with ERβ mRNA expression. Molecular docking analysis showed that ERα and ERβ have different binding interactions with synthetic antiestrogens, whereas the best inhibitor was Ral2 to ERα and Aco1 to ERβ. Thus, both inhibitors could be used as leads in further investigation of ERα, ERβ inhibitory activities in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is a disease that affects thousands of women around the world. Adequate treatment depends on the characterization of breast cancer subtypes. Tumors that are positive for the estrogen receptor represent the most common subtypes and have the best prognosis. However, many patients relapse due to resistance to tamoxifen, one of the main drugs used for these subtypes. In this study, our goal is to discuss a class of molecules that have been directly linked to the tamoxifen resistance process but is still underexplored: the non-coding RNAs (ncRNAs). We have reviewed ncRNAs that have been associated with different processes of resistance to tamoxifen in order to stimulate a discussion about the importance of knowing and understanding the role of these molecules in breast cancer and their relevance to clinical applications. Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer mortality among women. Two thirds of patients are classified as hormone receptor positive, based on expression of estrogen receptor alpha (ERα), the main driver of breast cancer cell proliferation, and/or progesterone receptor, which is regulated by ERα. Despite presenting the best prognosis, these tumors can recur when patients acquire resistance to treatment by aromatase inhibitors or antiestrogen such as tamoxifen (Tam). The mechanisms that are involved in Tam resistance are complex and involve multiple signaling pathways. Recently, roles for microRNAs and lncRNAs in controlling ER expression and/or tamoxifen action have been described, but the underlying mechanisms are still little explored. In this review, we will discuss the current state of knowledge on the roles of microRNAs and lncRNAs in the main mechanisms of tamoxifen resistance in hormone receptor positive breast cancer. In the future, this knowledge can be used to identify patients at a greater risk of relapse due to the expression patterns of ncRNAs that impact response to Tam, in order to guide their treatment more efficiently and possibly to design therapeutic strategies to bypass mechanisms of resistance. [ABSTRACT FROM AUTHOR]

To investigate the role of PR isoforms on the homeostasis of stem cells in the normal and neoplastic mammary gland, we used PRA and PRB transgenic mice and the T47D human breast cancer cell line and its derivatives, T47D YA and YB (manipulated to express only PRA or PRB, respectively). Flow cytometry and mammosphere assays revealed that in murine breast, overexpression of PRB leads to an increase in luminal and basal progenitor/stem cells. Ovariectomy had a negative impact on the luminal compartment and induced an increase in mammosphere-forming capacity in cells derived from WT and PRA mice only. Treatment with ICI 182,780 augmented the mammosphere-forming capacity of cells isolated from WT and PRA mice, whilst those from PRB remained unaltered. T47D YB cells showed an increase in the CD44+/CD24Low/− subpopulation; however, the number of tumorspheres did not vary relative to T47D and YA, even though they were larger, more irregular, and had increased clonogenic capacity. T47D and YA tumorspheres were modulated by estrogen/antiestrogens, whereas YB spheres remained unchanged in size and number. Our results show that alterations in PR isoform balance have an impact on normal and tumorigenic breast progenitor/stem cells and suggest a key role for the B isoform, with implications in response to antiestrogens. [ABSTRACT FROM AUTHOR]