Exploring the Spatial Landscape of the Estrogen Receptor Proximal Proteome With Antibody-Based Proximity Labeling.

Estrogen receptor α (ERα) drives the transcription of genes involved in breast cancer (BC) progression, relying on coregulatory protein recruitment for its transcriptional and biological activities. Mutation of ERα as well as aberrant recruitment of its regulatory proteins contribute to tumor adaptation and drug resistance. Therefore, understanding the dynamic changes in ERα protein interaction networks is crucial for elucidating drug resistance mechanisms in BC. Despite progress in studying ERα-associated proteins, capturing subcellular transient interactions remains challenging and, as a result, significant number of important interactions remain undiscovered. In this study, we employed biotinylation by antibody recognition (BAR), an innovative antibody-based proximity labeling (PL) approach, coupled with mass spectrometry to investigate the ERα proximal proteome and its changes associated with resistance to aromatase inhibition, a key therapy used in the treatment of ERα-positive BC. We show that BAR successfully detected most of the known ERα interactors and mainly identified nuclear proteins, using either an epitope tag or endogenous antibody to target ERα. We further describe the ERα proximal proteome rewiring associated with resistance applying BAR to a panel of isogenic cell lines modeling tumor adaptation in the clinic. Interestingly, we find that ERα associates with some of the canonical cofactors in resistant cells and several proximal proteome changes are due to increased expression of ERα. Resistant models also show decreased levels of estrogen-regulated genes. Sensitive and resistant cells harboring a mutation in the ERα (Y537C) revealed a similar proximal proteome. We provide an ERα proximal protein network covering several novel ERα-proximal partners. These include proteins involved in highly dynamic processes such as sumoylation and ubiquitination difficult to detect with traditional protein interaction approaches. Overall, we present BAR as an effective approach to investigate the ERα proximal proteome in a spatial context and demonstrate its application in different experimental conditions.

Estrogen receptor activation remodels TEAD1 gene expression to alleviate hepatic steatosis.

Sex-based differences in obesity-related hepatic malignancies suggest the protective roles of estrogen. Using a preclinical model, we dissected estrogen receptor (ER) isoform-driven molecular responses in high-fat diet (HFD)-induced liver diseases of male and female mice treated with or without an estrogen agonist by integrating liver multi-omics data. We found that selective ER activation recovers HFD-induced molecular and physiological liver phenotypes. HFD and systemic ER activation altered core liver pathways, beyond lipid metabolism, that are consistent between mice and primates. By including patient cohort data, we uncovered that ER-regulated enhancers govern central regulatory and metabolic genes with clinical significance in metabolic dysfunction-associated steatotic liver disease (MASLD) patients, including the transcription factor TEAD1. TEAD1 expression increased in MASLD patients, and its downregulation by short interfering RNA reduced intracellular lipid content. Subsequent TEAD small molecule inhibition improved steatosis in primary human hepatocyte spheroids by suppressing lipogenic pathways. Thus, TEAD1 emerged as a new therapeutic candidate whose inhibition ameliorates hepatic steatosis.

HOXA9 forms a repressive complex with nuclear matrix-associated protein SAFB to maintain acute myeloid leukemia.

HOXA9 is commonly upregulated in acute myeloid leukemia (AML), in which it confers a poor prognosis. Characterizing the protein interactome of endogenous HOXA9 in human AML, we identified a chromatin complex of HOXA9 with the nuclear matrix attachment protein SAFB. SAFB perturbation phenocopied HOXA9 knockout to decrease AML proliferation, increase differentiation and apoptosis in vitro, and prolong survival in vivo. Integrated genomic, transcriptomic, and proteomic analyses further demonstrated that the HOXA9-SAFB (H9SB)-chromatin complex associates with nucleosome remodeling and histone deacetylase (NuRD) and HP1γ to repress the expression of factors associated with differentiation and apoptosis, including NOTCH1, CEBPδ, S100A8, and CDKN1A. Chemical or genetic perturbation of NuRD and HP1γ-associated catalytic activity also triggered differentiation, apoptosis, and the induction of these tumor-suppressive genes. Importantly, this mechanism is operative in other HOXA9-dependent AML genotypes. This mechanistic insight demonstrates the active HOXA9-dependent differentiation block as a potent mechanism of disease maintenance in AML that may be amenable to therapeutic intervention by targeting the H9SB interface and/or NuRD and HP1γ activity.

Involvement of estrogen receptor activation in kaempferol-3-O-glucoside's protection against aging-related cognition impairment and microglial inflammation.

Estrogens have been demonstrated to inhibit age-related cognitive decline via binding to estrogen receptors (ERs). As a natural flavonoid component of Cuscuta Chinensis Lam., Kaempferol-3-O-glucoside (K-3-G) not only possesses anti-neuroinflammatory potential but also functions as an agonist for ERα and ERß. This study aimed to determine whether K-3-G improved cognition during the aging process, with an emphasis on its effect on microglial inflammation. In vivo, K-3-G (5 or 10 mg/kg/day) was orally given to the senescence-accelerated mouse prone 8 (SAMP8) mice from six to eight-month old. In addition to mitigating the memory and learning deficits of SAMP8 mice, K-3-G upregulated the expression of ERα and ERß in their hippocampal CA1 region, with the higher dose being more effective. Less Iba-1+ microglial cells presented in SAMP8 mice treated with K-3-G. The formation of NLR Family Pyrin Domain Containing 3 (NLRP3) complex, production of pro-inflammatory cytokines and oxidative stress-related markers, as well as expression of pro-apoptotic proteins were reduced by K-3-G. In vitro, BV2 microglial cells exposed to oligomeric amyloid beta (Aß)1-42 were treated with 100 µM K-3-G. K-3-G showed similar anti-inflammatory effects on BV2 cells as in vivo. K-3-G-induced alterations were partly diminished by fulvestrant, an ER antagonist. Moreover, dual-luciferase reporter system demonstrated that K-3-G induced ER expression by activating the transcription of estrogen-response elements (EREs). Collectively, these findings demonstrate that K-3-G may be a novel therapeutic agent for senescence-related cognitive impairment by inhibiting microglial inflammation through its action on ERs.

ENDORSE: a prognostic model for endocrine therapy in estrogen-receptor-positive breast cancers.

Advanced and metastatic estrogen receptor-positive (ER+ ) breast cancers are often endocrine resistant. However, endocrine therapy remains the primary treatment for all advanced ER+ breast cancers. Treatment options that may benefit resistant cancers, such as add-on drugs that target resistance pathways or switching to chemotherapy, are only available after progression on endocrine therapy. Here we developed an endocrine therapy prognostic model for early and advanced ER+ breast cancers. The endocrine resistance (ENDORSE) model is composed of two components, each based on the empirical cumulative distribution function of ranked expression of gene signatures. These signatures include a feature set associated with long-term survival outcomes on endocrine therapy selected using lasso-regularized Cox regression and a pathway-based curated set of genes expressed in response to estrogen. We extensively validated ENDORSE in multiple ER+ clinical trial datasets and demonstrated superior and consistent performance of the model over clinical covariates, proliferation markers, and multiple published signatures. Finally, genomic and pathway analyses in patient data revealed possible mechanisms that may help develop rational stratification strategies for endocrine-resistant ER+ breast cancer patients.

The infinite potential of a single substance: The history of tamoxifen as an example of drug repositioning / Nieskonczony potencjal jednej substancji: Historia tamoksyfenu jako przyklad repozycjonowania leków.

Known for a long time, well-tested substances are still finding new applications in science, medicine and industry. This is a popular and cost-effective strategy because, when searching for new applications, effective methods of their large-scale production and pharmacological activity, and the results of pharmacokinetic and toxicological studies are usually already known. Tamoxifen is known mainly as a drug used in the treatment of estrogen receptor-dependent breast cancer. Despite the discovery of this effective and profitable property many years ago and the constant expansion of related applications and patents, completely new ways of using tamoxifen and its derivatives in various fields continue to appear, and the number of patents for novel applications unrelated to breast cancer remains high. The aim of this article is to illustrate drug repositioning on the example of tamoxifen and to bring the ever-developing story of discoveries related to it to a wider audience.

Labeling of a mutant estrogen receptor with an Affimer in a breast cancer cell line.

Mutations of the intracellular estrogen receptor alpha (ERα) is implicated in 70% of breast cancers. Therefore, it is of considerable interest to image various mutants (L536S, Y537S, D538G) in living cancer cell lines, particularly as a function of various anticancer drugs. We therefore developed a small (13 kDa) Affimer, which, after fluorescent labeling, is able to efficiently label ERα by traveling through temporary pores in the cell membrane, created by the toxin streptolysin O. The Affimer, selected by a phage display, predominantly labels the Y537S mutant and can tell the difference between L536S and D538G mutants. The vast majority of Affimer-ERαY537S is in the nucleus and is capable of an efficient, unrestricted navigation to its target DNA sequence, as visualized by single-molecule fluorescence. The Affimer can also differentiate the effect of selective estrogen receptor modulators. More generally, this is an example of a small binding reagent-an Affimer protein-that can be inserted into living cells with minimal perturbation and high efficiency, to image an endogenous protein.

An aggressive lactotroph pituitary tumor in a young male: A pituitary carcinoma without metastasis.

This case report concerns a 31-year-old male with an aggressive pituitary tumor who presented initially with bitemporal hemianopsia and slightly elevated prolactin. On magnetic resonance imaging of the brain, there was a sellar mass with parasellar invasion to the lateral aspects of the internal carotid arteries, compressing the optic chiasm. On histopathological analysis, the diagnosis was made of a densely granulated lactotroph pituitary tumor with a Ki67 proliferation rate of 15%, a mitotic count of 6/10 high-power fields, and p53 positivity. Based on these features, the tumor was classified as a grade 2b tumor according to the Trouillas classification, and a more aggressive behavior of the tumor could be expected. In order to anticipate a future need for alternative drug treatments, the following analyses were undertaken: MGMT methylation (present) as well as the expression of estrogen receptor (negative), programmed-death ligand 1 (60 - 70% positive tumor cells), vascular endothelial growth factor-A and somatostatin receptor 2 (both positive). There was regrowth of residual tumor tissue, and the treatment consisted thus far of repeat surgery, cabergoline, pasireotide, and radiotherapy. Chemotherapy with temozolomide could not yet be initiated due to a concurrent infertility treatment. This case is unique because the tumor displays atypical characteristics, both in terms of morphology and behavior. It also illustrates how pathologists can play an important role in determining the diagnosis, prognosis, and possibilities for targeted therapy.

Correlation between CA12 and TFF3 and their prediction value of neoadjuvant chemotherapy response in breast cancer.

WHAT IS KNOWN AND OBJECTIVE: Compared with other molecular subtypes, hormone receptor-positive breast cancer often shows worse neoadjuvant chemotherapy efficacy. This study aims to explore the relationship between the oestrogen receptor (ER)-related genes carbonic anhydrase 12 (CA12) and trefoil factor 3 (TFF3) and their predictive value of neoadjuvant chemotherapy for breast cancer. METHODS: We investigated the relationships between CA12, TFF3 and ER status and their predictive value of anthracycline-taxane neoadjuvant chemotherapy in 115 female breast cancer patients via real-time polymerase chain reaction (RT-PCR) and 4 GEO datasets: GSE41998, GSE25065, GSE20194 and GSE20271. Then, the effects of CA12 and TFF3 on the chemotherapy drugs doxorubicin and docetaxel were verified in vitro in the breast cancer cell lines MCF-7 and BT474. RESULTS AND DISCUSSION: The GEO datasets and RT-PCR results showed that the relative expression of both CA12 and TFF3 was higher in oestrogen receptor-positive samples compared with the other samples (p < 0.05). CA12 was significantly correlated with TFF3 (p < 0.05). In MCF-7 cells, inhibition of TFF3 induced downregulation of CA12 and ESR1 (p < 0.05) at both the mRNA and the protein levels, while inhibition of CA12 also downregulated TFF3 and ESR1 (p < 0.05). In BT474 cells, inhibition of TFF3 downregulated CA12 and ESR1 (p < 0.05) at both the mRNA and the protein levels, while inhibition of CA12 led to slight upregulation of TFF3 and ESR1 (p > 0.05). Moreover, GEO datasets and RT-PCR results showed that CA12 and TFF3 were more highly expressed in nonpathological complete response (non-pCR) samples than in pCR samples (p < 0.05). Cell viability assays of MCF-7 and BT474 cells showed that inhibiting CA12 and TFF3 could enhance sensitivity to doxorubicin and docetaxel (p < 0.05). WHAT IS NEW AND CONCLUSION: CA12 and TFF3 were correlated with each other, and their high expression might explain the worse efficacy of neoadjuvant chemotherapy in oestrogen receptor-positive breast cancer patients.

Efficacy and Safety of CDK4/6 Inhibitors Combined with Endocrine Therapy in HR+/HER-2- ABC Patients: A Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate the efficacy and safety of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors combined with endocrine therapy (ET) for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER-2-) advanced breast cancer (ABC) patients. METHODS: We searched clinical trials of CDK4/6 inhibitors combined with ET and calculated the clinical outcomes. RESULTS: HR+/HER-2- ABC patients treated with CDK4/6 inhibitors combined with ET had significantly prolonged progression-free survival (PFS) and improved objective response rate (ORR) and clinical benefit rate (CBR). CONCLUSIONS: CDK4/6 inhibitors combined with ET can bring more clinical benefits to ABC patients, and the safety profile is acceptable.

Factors affecting locoregional recurrence in breast cancer patients undergoing surgery following neoadjuvant treatment.

BACKGROUND: Neoadjuvant chemotherapy (NAC) has been the standard treatment for locally advanced breast cancer for the purpose of downstaging or for conversion from mastectomy to breast conservation surgery (BCS). Locoregional recurrence (LRR) rate is still high after NAC. The aim of this study was to determine predictive factors for LRR in breast cancer patients in association with the operation types after NAC. METHODS: Between 2005 and 2017, 1047 breast cancer patients underwent BCS or mastectomy after NAC in Chang Gung Memorial Hospital, Linkou. We obtained data regarding patient and tumor characteristics, chemotherapy regimens, clinical tumor response, tumor subtypes and pathological complete response (pCR), type of surgery, and recurrence. RESULTS: The median follow-up time was 59.2 months (range 3.13-186.75 months). The mean initial tumor size was 4.89 cm (SD ± 2.95 cm). Of the 1047 NAC patients, 232 (22.2%) achieved pCR. The BCS and mastectomy rates were 41.3% and 58.7%, respectively. One hundred four patients developed LRR (9.9%). Comparing between patients who underwent BCS and those who underwent mastectomy revealed no significant difference in the overall LRR rate of the two groups, 8.8% in BCS group vs 10.7% in mastectomy group (p = 0.303). Multivariate analysis indicated that independent factors for the prediction of LRR included clinical N2 status, negative estrogen receptor (ER), and failure to achieve pCR. In subgroups of multivariate analysis, only negative ER was the independent factor to predict LRR in mastectomy group (p = 0.025) and hormone receptor negative/human epidermal growth factor receptor 2 positive (HR-/HER2 +) subtype (p = 0.006) was an independent factor to predict LRR in BCS patients. Further investigation according to the molecular subtype showed that following BCS, non-pCR group had significantly increased LRR compared with the pCR group, in HR-/HER2 + subtype (25.0% vs 8.3%, p = 0.037), and HR-/HER2- subtype (20.4% vs 0%, p = 0.002). CONCLUSION: Clinical N2 status, negative ER, and failure to achieve pCR after NAC were independently related to the risk of developing LRR. Operation type did not impact on the LRR. In addition, the LRR rate was higher in non-pCR hormone receptor-negative patients undergoing BCS comparing with pCR patients.

Targeting estrogen receptors in colorectal cancer.

Hormones have become a useful therapeutic aspect of clinical endocrinology but how to use them to optimize the health benefits and avoid adverse effects is a major challenge. Estrogen is an indispensable hormone for proper biological functioning but is also implicated with the pathology of both the reproductive and non-reproductive tissues. Abnormal estrogen receptor signaling may increase the risk of development of a variety of diseases including colorectal cancer (CRC). Estrogen receptor beta (ERß) is the predominant subtype in the colonic epithelium and confers the anti-tumor effect through various mechanisms. Many investigators have embarked on the search for the biological mechanisms by which estrogen and estrogen-like compounds may influence the pathogenesis of CRC. This review explores the recent findings on the therapeutic role of ERß in the colonic epithelium as a prospective candidate for targeted endocrine therapy in CRC.

Systemic Therapies for Nonmetastatic Breast Cancer: The Role of Neoadjuvant and Adjuvant Chemotherapy and the Use of Endocrine Therapy.

Breast cancer is a heterogenous disease, comprised of at least 3 major subtypes: hormone receptor-positive/HER2-(HR+), HER2+, and HR-/HER2-(triple negative) breast cancers. The medical management of each subype is distinct. In this article, we review contemporary data supporting the use of chemotherapy, endocrine therapy and biologic therapies, especially HER2-directed agents, in the adjuvant and neoadjuvant setting in patients with newly diagnosed nonmetastatic (stage I-III) breast cancer.

Breast density reduction as a predictor for prognosis in premenopausal women with estrogen receptor-positive breast cancer: an exploratory analysis of the updated ASTRRA study.

BACKGROUND: While the relationship between mammographic breast density reduction (MDR) and endocrine therapy efficacy has been reported in estrogen receptor (ER)-positive breast cancer, it is still unclear in premenopausal women, especially in the case of adding ovarian function suppression (OFS) to antihormone therapy. The authors investigated the impact of MDR on prognosis stratified by treatment based on the updated results of the ASTRRA trial. MATERIALS AND METHODS: The ASTRRA trial, a randomized phase III study, showed that adding OFS to tamoxifen (TAM) improved survival in premenopausal women with estrogen receptor-positive breast cancer after chemotherapy. The authors updated survival outcomes and assessed mammography before treatment and the annual follow-up mammography for up to 5 years after treatment initiation. Mammographic density (MD) was classified into four categories based on the Breast Imaging-Reporting and Data System. MDR-positivity was defined as a downgrade in MD grade on follow-up mammography up to 2 years after randomization, with pretreatment MD grade as a reference. RESULTS: The authors evaluated MDR in 944 of the 1282 patients from the trial, and 813 (86.2%) had grade III or IV MD. There was no difference in the MDR-positivity rate between the two treatment groups [TAM-only group (106/476 (22.3%)) vs. TAM+OFS group (89/468 (19.0%)); P =0.217). MDR-positivity was significantly associated with better disease-free survival (DFS) in the TAM+OFS group (estimated 8-year DFS: 93.1% in MDR-positive vs. 82.0% in MDR-negative patients; HR: 0.37; 95% CI: 0.16-0.85; P =0.019), but not in the TAM-only group ( Pinteraction =0.039). MDR-positive patients who received TAM+OFS had a favorable DFS compared to MDR-negative patients who received only TAM (HR: 0.30; 95% CI: 0.13-0.70; P =0.005). CONCLUSION: Although the proportion of MDR-positive patients was comparable between both treatment groups, MDR-positivity was independently associated with favorable outcomes only in the TAM+OFS group.

Utilization and outcomes of the 21-gene recurrence score in de novo metastatic breast cancer.

BACKGROUND: Limited data exist regarding the utility and validity of the 21-gene recurrence score (RS) in patients with de novo metastatic breast cancer (dnMBC). This study aimed to investigate the practice patterns as well as associated survival outcomes based on 21-gene RS in dnMBC. RESEARCH DESIGN AND METHODS: The Surveillance, Epidemiology, and End Results Oncotype database was queried for women with hormone receptor-positive and Her2-negative dnMBC. RESULTS: A total of 153 patients were identified, including 62.7% and 37.3% of patients who had RS < 26 and ≥ 26, respectively. Patients with RS ≥ 26 were more likely to receive chemotherapy compared to those with RS < 26 (61.4% vs. 28.1%, p < 0.001). Patients with RS ≥ 26 had an inferior breast cancer-specific survival (BCSS) (2-year BCSS: 84.3% vs. 89.5, p = 0.067) and overall survival (OS) compared to those with RS < 26 (2-year OS: 76.9% vs. 87.4%, p = 0.018). The multivariate Cox proportional hazard models showed that those with RS ≥ 26 had a significantly inferior BCSS (hazard ratio [HR] 2.251, 95% confidence interval [CI] 1.056-4.799, p = 0.036) and OS (HR 2.151, 95%CI 1.123-4.120, p = 0.021) compared to those with RS < 26. CONCLUSIONS: The 21-gene RS assay is an important prognostic factor in patients with dnMBC.

Role of G-protein-coupled estrogen receptor in the pathogenesis of chronic asthma.

BACKGROUND AND AIM: G protein-coupled estrogen receptor (GPER) is an estrogen receptor located on the plasma membrane. We previously reported that the administration of G-1, a GPER-specific agonist, suppressed development of acute ovalbumin (OVA)-induced asthma in a mouse model. Herein, we evaluate the involvement of GPER in a mouse model of chronic OVA asthma. METHODS: G-1 or saline was administered subcutaneously to BALB/c mice with chronic OVA asthma, and pathological and immunological evaluation was performed. In addition, Foxp3-expressing CD4-positive T-cells in the spleen and ILC2 in the lungs were measured using flow cytometry. RESULTS: We observed a significant decrease in the number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) in the G-1 treated group. In the airways, inflammatory cell accumulation, Th2 cytokines (IL-4, IL-5, IL-13, and eotaxin) and epithelial cytokine TSLP were suppressed, while in the BALF, anti-inflammatory cytokines (IL-10 and TGF-ß) were increased. Furthermore, in splenic mononuclear cells, Foxp3-expressing CD4-positive T-cells were increased in the G-1 group, whereas treatment with G-1 did not change the percentage of ILC2 in the lungs. CONCLUSION: G-1 administration suppressed allergic airway inflammation in mice with chronic OVA asthma. GPER may be a potential therapeutic target for chronic allergic asthma.

Women's Health Update: Growing Role of PET for Patients with Breast Cancer.

Positron Emission Tomography (PET) has been growing in usage for patients with breast cancer, due to an increased number of FDA-approved PET radiotracers pertinent to patients with breast cancer as well as increased prospective evidence for the value of these agents. The leading PET radiotracer for patients with breast cancer is 18F-fluorodeoxyglucose (18F-FDG), which measures glucose metabolism. There is prospective evidence for the use of 18F-FDG PET in systemic staging of newly diagnosed locally advanced breast cancer (stages IIB-IIIC), monitoring breast cancer treatment response, and detecting breast cancer recurrence, particularly in no special type (NST) breast cancer. 16α-18F-fluoro-17ß-Fluoroestradiol (18F-FES) is a radiolabeled estrogen which evaluates estrogen receptor (ER) accessible for estrogen binding. There is prospective evidence supporting 18F-FES PET as a predictive biomarker for selecting patients with metastatic breast cancer for endocrine therapies. 18F-FES PET has also been shown to be valuable in the evaluation of ER status of lesions which are difficult to biopsy, for evaluation of ER status in lesions that are equivocal on other imaging modalities, and for selecting optimal dosage of novel ER-targeted systemic therapies in early clinical trials. Multiple investigators have suggested 18F-FES PET will have an increasing role for patients with invasive lobular breast cancer (ILC), which is less optimally evaluated by 18F-FDG PET. Sodium 18F-Fluoride (18F-NaF) evaluates bone turnover and has been effective in evaluation of malignancies which commonly metastasize to bone. In patients with metastatic breast cancer, 18F-NaF PET/CT has demonstrated superior sensitivity for osseous metastases than 99mTc-MDP or CT. In addition to these three FDA-approved PET radiotracers, there are multiple novel radiotracers currently in clinical trials with potential to further increase PET usage for patients with breast cancer.

Nanomedicine in therapeutic warfront against estrogen receptor-positive breast cancer.

Breast cancer (BC) is the most frequently diagnosed malignancy in women worldwide. Almost 70-80% of cases of BC are curable at the early non-metastatic stage. BC is a heterogeneous disease with different molecular subtypes. Around 70% of breast tumors exhibit estrogen-receptor (ER) expression and endocrine therapy is used for the treatment of these patients. However, there are high chances of recurrence in the endocrine therapy regimen. Though chemotherapy and radiation therapy have substantially improved survival rates and treatment outcomes in BC patients, there is an increased possibility of the development of resistance and dose-limiting toxicities. Conventional treatment approaches often suffer from low bioavailability, adverse effects due to the non-specific action of chemotherapeutics, and low antitumor efficacy. Nanomedicine has emerged as a conspicuous strategy for delivering anticancer therapeutics in BC management. It has revolutionized the area of cancer therapy by increasing the bioavailability of the therapeutics and improving their anticancer efficacy with reduced toxicities on healthy tissues. In this article, we have highlighted various mechanisms and pathways involved in the progression of ER-positive BC. Further, different nanocarriers delivering drugs, genes, and natural therapeutic agents for surmounting BC are the spotlights of this article.

Advances in Medicinal Chemistry of Estrogen-related Receptor Alpha (ERRα) Inverse Agonists.

Estrogen-related receptor alpha (ERRα), a member of the nuclear receptor superfamily, is strongly expressed in breast cancer cells. Its overexpression is associated with poor prognosis in triple- negative Breast Cancer (TNBC). ERRα expression could be inhibited by the downregulation of upstream oncogenic growth factors mTOR, HER2, and PI3K. Low expression of ERRα could suppress the migration and angiogenesis of tumor cells by inhibiting the activity of its downstream signals VEGF and WNT11. Studies have confirmed that ERRα inverse agonists can inhibit ERRα expression to treat breast cancer. Inverse agonists of ERRα could disrupt the interactions of ERRα with its coactivators and inhibit tumor development. Existing ERRα inverse agonists have shown moderate efficacy in inhibiting the growth of breast cancer cells. Clinical inverse agonists of ERRα have not been found in the literature. This review focuses on the research progress and the structureactivity relationship of ERRα inverse agonists, providing guidance for the research and discovery of new anti-tumor compounds for TNBC.

Targeting autophagy with tamoxifen in breast cancer: From molecular mechanisms to targeted therapy.

BACKGROUND: Tamoxifen (TAM) is often recommended as a first-line treatment for estrogen receptor-positive breast cancer (BC). However, TAM resistance continues to be a medical challenge for BC with hormone receptor positivity. The function of macro-autophagy and autophagy has recently been identified to be altered in BC, which suggests a potential mechanism for TAM resistance. Autophagy is a cellular stress-induced response to preserve cellular homeostasis. Also, therapy-induced autophagy, which is typically cytoprotective and activated in tumor cells, could sometimes be non-protective, cytostatic, or cytotoxic depending on how it is regulated. OBJECTIVE: This review explored the literature on the connections between hormonal therapies and autophagy. We investigated how autophagy could develop drug resistance in BC cells. METHODS: Scopus, Science Direct, PubMed, and Google Scholar were used to search articles for this study. RESULTS: The results demonstrated that protein kinases such as pAMPK, BAX, and p-p70S6K could be a sign of autophagy in developing TAM resistance. According to the study's findings, autophagy plays an important role in BC patients' TAM resistance. CONCLUSION: Therefore, by overcoming endocrine resistance in estrogen receptor-positive breast tumors, autophagy inhibition may improve the therapeutic efficacy of TAM.