A series of ER-PROTACs compounds were designed, synthesized and tested for their ability to degrade estrogen receptor proteins and exhibit Human breast cancer cells (MCF-7) inhibition activity. Molecular docking simulations were performed using Discovery studio. Among these compounds, QDE-003-W had the highest estrogen receptor protein degradation ability and cellular activity, with a DC50 value of 95 nM, for estrogen receptor protein degradation and an IC50 value of 30.2 nM for cellular activity. Furthermore, the molecular docking study revealed that the biological activity of QDE-003-W depended on its suitable linker length, which gave us some reference significance for the study of ER-PROTACs. And compared with fulvestrant, QDE-003-W exhibited more favorable pharmacokinetic (PK) characteristics. No significant adverse side effects were observed under the administration protocol, which indicates that the tested mice had excellent tolerance to both the administration method and the dosage. Such favorable PK characteristics and safety features further enhance the prospects of QDE-003-W as a viable candidate for subsequent preclinical and clinical development.

Seventy percent of newly diagnosed breast cancers are estrogen receptor-α positive and HER2/neu negative. First-line treatments incorporate endocrine therapy and cyclin-dependent kinase 4/6 inhibitors. However, therapy resistance occurs in most patients. Hence, there is an urgent need for effective second-line treatments. We previously showed that the potent estrogen receptor-β agonists, OSU-ERβ-12 and LY500307, synergized with the selective estrogen receptor modulator, tamoxifen, in vitro. Furthermore, we showed that these compounds inhibited endocrine-resistant and cyclin-dependent kinase 4/6-inhibitor-resistant estrogen receptor α-positive cell lines in vitro. Here, we used fulvestrant- and abemaciclib-resistant T47D-derived cell line xenografts to determine the efficacy of the combination of OSU-ERβ-12 and LY500307 with tamoxifen in vivo.

Despite efficacy in vitro, treatments failed to reduce xenograft tumor volumes. Hence, we conclude that this treatment strategy lacks direct cancer cell-intrinsic cytotoxic efficacy in vivo.

Despite endocrine therapy (ET), approximately 20-40% of Stage I-III estrogen receptor-positive breast cancer (ER + BC) patients experience recurrence. Recurrence while on ET is indicative of ET resistance. This study aimed to identify differentially expressed genes (DEGs) associated with recurrence during ET (ET resistance) and to explore gene expression differences across PAM50 molecular subtypes. Eighty tumor specimens from 79 patients treated at the City of Hope Comprehensive Cancer Center (2012-2016) were analyzed using NanoString technology. Fourteen patients (17.7%) experienced recurrence over a median follow-up of 68 months (range 35-104 months). Key upregulated DEGs in the recurrence group included EZH2 (log2 fold change[log2FC]: 0.67, p = 0.0017), WNT11 (log2FC: 1.08, p = 0.0088), ITGB6 (log2FC: 0.80, p = 0.0312), and TOP2A (log2FC: 0.79, p = 0.0381). Downregulated DEGs included SNAI2 (log2FC: - 0.63, p = 0.0055), ITPR1 (log2FC: - 0.75, p = 0.0083), CD10 (log2FC: - 0.70, p = 0.0092), PTEN (log2FC: - 0.29, p = 0.0163), VRD (log2FC: - 0.46, p = 0.0184), and WNT5A (log2FC: - 0.76, p = 0.0272). EZH2 and TOP2A were positively correlated with proliferation scores, while WNT11 and ITGB6 emerged as potential biomarkers independently associated with recurrence. These findings suggest novel biomarker candidates that could help overcome ET resistance, reduce recurrence, and improve outcomes in ER + BC.

In the breast tumor microenvironment (TME), adipocytes exert a selective pressure on the behavior of breast cancer stem cells (BCSCs), which are involved in endocrine therapy resistance. In obesity, adipocytes secrete reduced levels of adiponectin, which promotes the growth and progression of ERα-positive breast cancer (BC). Here, we examined how low adiponectin levels affect the enrichment of the BCSC subpopulation and the mechanisms contributing to the maintenance of endocrine therapy resistance in BC. Flow cytometry, qRT-PCR, and Western blotting analysis were performed to assess stemness, the cell cycle, and apoptosis markers in MCF-7 wild-type (WT) and tamoxifen-resistant (TR) mammospheres. nLC-MS/MS was employed to profile and compare the proteome of BCSCs. Differentially expressed proteins were intersected with data from the MetacoreTM dataset. Our study demonstrated that adiponectin increased the percentage of CD44+/CD24-/ALDH1+ stem-like cells in TR MCF-7 mammospheres. Specifically, adiponectin contributed to the maintenance of BCSC bulk in TR MCF-7 cells through a slow cycling rate, supported by decreased levels of Cyclin D1 and Ki67 and increased p21 and p27 expression, and through escape from apoptosis, sustained by reduced ROS production and preserved maintenance of mitochondrial membrane potential. Our results provide new insights into the contribution of adiponectin to poor ERα-positive BC outcomes. Deeply understanding adiponectin's role in stemness may disclose novel therapeutic approaches to treat hormone-resistant obese BC patients.

ER/PR+HER2- breast tumours are the most predominant subtype of breast cancer worldwide, including India. Unlike TNBCs, these tumours can be treated with anti-estrogens or aromatase inhibitors. Despite the success of endocrine therapy, a fraction of patients with ER/PR+ breast tumours do not respond to hormone-receptor-specific treatment and encounter disease recurrence contributing to their poor survival. The genomic underpinnings of therapy resistance in ER/PR+HER2- breast tumours are incompletely understood. We have performed whole genome sequencing (WGS) from tumour and normal tissue samples from endocrine-therapy resistant ER/PR+HER2- breast cancer patients who have relapsed on endocrine therapy and have conducted a comparative analysis of WGS data generated from tissues of endocrine therapy sensitive patients who remained free of disease during a minimum 5-year follow-up. Our analysis shows (a) a three-gene (PIK3CA-ESR1-TP53) resistance signature, and (b) impaired DNA double-strand break repair and homologous recombination pathways, were significantly associated with endocrine-therapy resistance and disease recurrence in ER/PR+HER2- tumours. Genome instability, contributing to high burden of copy-number, structural alterations and telomere-shortening identified as major markers of endocrine treatment resistance. Early prediction of endocrine-therapy resistance from the genomic landscape of breast tumours will aid therapeutics. Our finding also opens up the possibility of repurposing PARP inhibitors in treating endocrine therapy-resistant breast cancer patients.

Metastatic breast cancer (mBC) remains an incurable disease, and most patients will experience disease progression during their treatment course. Although endocrine therapy remains the mainstay of treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative mBC, significant progress has been and continues to be made in the treatment of this BC subtype. The discovery of molecular markers, mutations in key cellular pathways, and genomic signatures have led to the development of novel and targeted agents, such as antibody-drug conjugates, oral selective estrogen receptor downregulators, and inhibitors of the PI3K/AKT/mTOR pathway. This has resulted in significant improvements in the survival and quality of life of patients. With the increasing number of treatment options for patients, appropriate drug sequencing remains a challenge. Treatment discussions should involve patient-physician shared decision making, with consideration of genomic data, previous lines of therapy, side effect profiles, and clinical trial enrollment.

Breast cancer is the most prevalent cancer type in Mexico, with male breast cancer accounting for only 1% of all breast cancer cases. A limited number of studies have described the clinical-pathological profiles of males with breast cancer in low- and middle-income countries. This study presents an analysis of patients with breast cancer seen at three different institutions in México.

A retrospective review of the medical records was performed to analyze the clinical and pathological characteristics of 49 men diagnosed with breast cancer and their overall survival.

The mean age at diagnosis was 64.65 years. A significant proportion of patients presented at diagnosis with stage IV disease (n = 11, 22.45%), had triple-negative subtype (n = 6, 12.24%), and nuclear grade III (n = 20, 40.8%). Primary endocrine resistance was observed in 10 patients (31.25%). Genetic analysis was performed on 24 patients (48.9%), revealing a germline BRCA pathogenic variant in 8.33%.

Our findings described the clinical and pathological profile of breast cancer in a male cohort in Mexico, with a significantly high proportion of advanced disease, triple-negative subtype, nuclear grade III, and endocrine resistance. Further comprehensive studies, including research into somatic mutations, are needed.

Hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer is the most common subtype. Abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6, was approved to reduce risk of recurrence in high-risk, HR+, HER2-, early breast cancer based on the monarchE trial. The most common adverse events reported in monarchE were diarrhea, neutropenia, and fatigue. Real-world tolerability data and incidence of adverse events with abemaciclib in the adjuvant setting versus the metastatic setting is lacking.

This is a retrospective analysis of HR+, HER2- breast cancer patients on abemaciclib from March 2018 to September 2021 at Robert H. Lurie Comprehensive Cancer Center in Chicago, Illinois. Incidence, grade of adverse events, dose reductions, and discontinuations were evaluated in patients taking abemaciclib in the adjuvant setting and the metastatic setting.

Of the 30 patients included in this analysis, 100% experienced an adverse event of any grade. During treatment, 12.5% treated in the adjuvant setting and 35.7% in the metastatic setting experienced grade ≥3 adverse events. Adverse events leading to discontinuation of abemaciclib occurred in 18.8% of patients in the adjuvant setting and 57.1% in the metastatic setting.

This data suggests abemaciclib is better tolerated in high-risk, HR+, HER2-, node-positive, early breast cancer treated in the adjuvant setting compared to the metastatic setting. Management of adverse events is crucial to help patients stay on therapy to improve clinical outcomes. Real-world tolerability of abemaciclib in both the adjuvant and metastatic settings is of importance.

Endocrine therapies targeting the estrogen receptor (ER/ESR1) are the cornerstone to treat ER-positive breast cancers patients, but resistance often limits their effectiveness. Notable progress has been made although the fragmented way data is reported has reduced their potential impact. Here, we introduce EstroGene2.0, an expanded database of its precursor 1.0 version. EstroGene2.0 focusses on response and resistance to endocrine therapies in breast cancer models. Incorporating multi-omic profiling of 361 experiments from 212 studies across 28 cell lines, a user-friendly browser offers comprehensive data visualization and metadata mining capabilities ( https://estrogeneii.web.app/ ). Taking advantage of the harmonized data collection, our follow-up meta-analysis revealed transcriptomic landscape and substantial diversity in response to different classes of ER modulators. Endocrine-resistant models exhibit a spectrum of transcriptomic alterations including a contra-directional shift in ER and interferon signalings, which is recapitulated clinically. Dissecting multiple ESR1-mutant cell models revealed the different clinical relevance of cell model engineering and identified high-confidence mutant-ER targets, such as NPY1R. These examples demonstrate how EstroGene2.0 helps investigate breast cancer's response to endocrine therapies and explore resistance mechanisms.

Despite proven therapy options for estrogen receptor-positive (ER+) breast tumors, a substantial number of patients with ER+ breast cancer exhibit relapse with associated metastasis. Loss of expression of RasGAPs leads to poor outcomes in several cancers, including breast cancer. Mining the The Cancer Genome Atlas (TCGA) breast cancer RNA-Seq dataset revealed that low expression of the RasGAP DAB2IP was associated with a significant decrease in relapse-free survival in patients with Luminal A breast cancer. Immunostaining demonstrated that DAB2IP loss occurred in grade 2 tumors and higher. Consistent with this, genes upregulated in DAB2IP-low Luminal A tumors were shared with more aggressive tumor subtypes and were associated with proliferation, metastasis, and altered ER signaling. Low DAB2IP expression in ER+ breast cancer cells was associated with increased proliferation, enhanced stemness phenotypes, and activation of IKK, the upstream regulator of the transcription factor NF-κB. Integrating cell-based ChIP-Seq with motif analysis and TCGA RNA-Seq data, we identified a set of candidate NF-κB target genes upregulated with loss of DAB2IP linked with several oncogenic phenotypes, including altered RNA processing. This study provides insight into mechanisms associated with aggressiveness and recurrence within a subset of the typically less aggressive Luminal A breast cancer intrinsic subtype.

The presence of epithelial-mesenchymal transition (EMT) in breast cancer (BC) cells has been linked to worse prognosis and may influence response to systemic treatment. We explored the effect of EMT in tumor samples of patients with metastatic BC on disease-free interval and overall survival in those patients receiving eribulin or cyclin-dependent kinase 4/6 inhibitors (CDK4/6i).

Key inclusion criteria included available archived primary BC tissue and, where available, matched metastatic biopsy. Patients received eribulin and/or a CDK4/6i in the metastatic setting. Specimens were assessed for biomarkers by immunohistochemistry (CDH1, AE1/3, VIM, CDH2, ZEB1, pSMAD2, and SMAD4) and gene expression by droplet digital polymerase chain reaction (CDH1, CDH2, SNAI1 & 2, TWIST1, VIM, PTEN, and ZEB1 & 2).

Between 2002 and 2020, 127 patients were included (95 early-stage disease at diagnosis with metastatic relapse, 32 de novo metastatic disease). In metastatic samples, presence of ZEB1 overexpression was associated with shorter time to recurrence (48.1 months shorter; P = .003), with pSMAD2 overexpression suggesting clinical significance of 52.0 months shorter; P = .01. High gene expression levels for SNAIL1, TWIST1, and PTEN in the primary BC were associated with significantly longer survival in patients who received eribulin (P < .05); high VIM was associated with a clinically relevant trend toward shorter survival after a CDK4/6i (P = .013).

We demonstrate in our exploratory study that biomarkers involved in the process of EMT could have a prognostic impact in a cohort of patients with BC uniformly treated and with long-term follow-up. Genes known to be involved in EMT were associated with improved eribulin efficacy, while suggesting a poorer outcome with CDK4/6i.

To compare CDK4/6 inhibitor (CDK4/6i) with endocrine therapy (ET) in the first- versus second-line setting for treatment of hormone receptor positive (HR+), HER2 negative, metastatic breast cancer (MBC) using real-world evidence.

Patients with HR+, HER2 negative MBC, diagnosed between 2/3/2015 and 11/2/2021 and having ≥ 3 months follow-up were identified from the nationwide electronic health record-derived Flatiron Health de-identified database. Treatment cohorts included: (1) first-line ET with a CDK 4/6i (1st-line CDK4/6i) versus (2) first-line ET alone followed by second-line ET with a CDK4/6i (2nd-line CDK4/6i). Differences in baseline characteristics were tested using chi-square tests and two-sample t-tests. Time to third-line therapy, time to start of chemotherapy, and overall survival were compared using Kaplan-Maier method.

The analysis included 2771 patients (2170 1st-line CDK4/6i and 601 2nd-line CDK4/6i). Patients receiving 1st-line CDK4/6i were younger (75% vs 68% < 75 years old, p = 0.0001), less likely uninsured or not having insurance status documented (10% vs. 13%, p = 0.04), of better performance status (50% vs 43% with ECOG 0, p = 0.03), and more likely to have de novo MBC (36% vs. 24%, p < 0.001). Time to third-line therapy (49 vs 22 months, p < 0.001) and time to chemotherapy (68 vs 41 months, p < 0.001) were longer in those receiving first-line CDK4/6i. Overall survival (54 vs 49 months, p = 0.33) was similar between groups.

Use of CDK4/6i with first-, vs second-, line ET was associated with longer time to receipt of 3rd-line therapy and longer time to receipt of chemotherapy.

Elacestrant significantly prolonged progression-free survival (PFS) with manageable safety versus standard-of-care (SOC) endocrine therapy (ET) in patients with estrogen receptor-positive (ER+), HER2- metastatic breast cancer and tumors harboring estrogen receptor 1 (ESR1) mutation following ET plus a cyclin-dependent kinase 4/6 inhibitor (ET+CDK4/6i). In patients with ESR1-mutated tumors, we evaluated the efficacy and safety of elacestrant versus SOC based on prior ET+CDK4/6i duration and in clinical subgroups with prior ET+CDK4/6i ≥12 months.

EMERALD, an open-label phase III trial, randomly assigned patients with ER+, HER2- metastatic breast cancer who had received 1-2 prior lines of ET, mandatory CDK4/6i, and ≤1 chemotherapy to elacestrant (345 mg daily) or SOC (aromatase inhibitor or fulvestrant). PFS was assessed across subgroups in post hoc exploratory analyses without adjustment for multiple testing.

In patients with ESR1-mutated tumors and prior ET+CDK4/6i ≥12 months, the median PFS for elacestrant versus SOC was 8.6 versus 1.9 months (HR, 0.41; 95% confidence interval, 0.26-0.63). In this population, the median PFS (in months) for elacestrant versus SOC was 9.1 versus 1.9 (bone metastases), 7.3 versus 1.9 (liver and/or lung metastases), 9.0 versus 1.9 (<3 metastatic sites), 10.8 versus 1.8 (≥3 metastatic sites), 5.5 versus 1.9 (PIK3 catalytic subunit α mutation), 8.6 versus 1.9 (tumor protein p53 gene mutation), 9.0 versus 1.9 (HER2-low), 9.0 versus 1.9 (ESR1D538G-mutated tumors), and 9.0 versus 1.9 (ESR1Y537S/N-mutated tumors). Subgroup safety was consistent with the overall population.

The duration of prior ET+CDK4/6i ≥12 months in metastatic breast cancer was associated with a clinically meaningful improvement in PFS for elacestrant compared with SOC and was consistent across all subgroups evaluated in patients with ER+, HER2-, ESR1-mutated tumors.

Low-grade serous ovarian carcinoma (LGSOC) is a rare subtype of epithelial ovarian cancer, characterized by a unique molecular background and specific clinical behavior. A growing body of molecular data underscores LGSOC as a distinct disease entity; however, clinical evidence on the optimal treatment regimens for LGSOC remains limited due to the low incidence of the disease. Consequently, treatment recommendations for LGSOC are still often derived from findings on the more common high-grade serous ovarian carcinoma (HGSOC) and typically focus on radical cytoreductive surgery and platinum-based chemotherapy. Since LGSOCs typically exhibit only limited responsiveness to platinum-based chemotherapy, the clinical management of advanced and recurrent LGSOCs remains a significant therapeutic challenge and often results in limited treatment options and suboptimal outcomes. Recent advances in molecular profiling and the identification of new, promising targets, such as the mitogen-activated protein kinase (MAPK) pathway, offer hope for improving both the prognosis and health-related quality of life in affected patients. Given the high unmet clinical need to establish new therapeutic standards beyond cytotoxic chemotherapy, this review aims to summarize the most promising molecular targets and emerging targeted agents.

The therapeutic landscape for hormone receptor-positive (HR+) breast carcinoma has undergone a significant transformation with the advent of cyclin-dependent kinase (CDK)4/6 inhibitors, particularly in combination with endocrine therapy as the primary regimen. However, the evolution of resistance mechanisms in response to CDK4/6 inhibitors in HR+ metastatic breast cancer presents substantial challenges in managing the disease. This review explores the diverse genomic landscape underlying resistance, including disturbances in the cell cycle, deviations in oncogenic signaling pathways, deficiencies in DNA damage response (DDR) mechanisms, and changes in the tumor microenvironment (TME). Additionally, it discusses potential strategies to surmount resistance, including advancements in endocrine therapy, targeted inhibition of cell cycle components, suppression of AKT/mTOR activation, exploration of the FGFR pathway, utilization of antibody-drug conjugates (ADCs), and integration of immune checkpoint inhibitors (ICIs) with endocrine therapy and CDK4/6 inhibitors, providing pathways for enhancing patient outcomes amidst treatment challenges.

Breast cancer is the most prevalent cancer in women globally. Over-activated estrogen receptor (ER) α signaling is considered the main factor in luminal breast cancers, which can be effectively managed with selective estrogen receptor modulators (SERMs) like tamoxifen. However, approximately 30-40% of ER + breast cancer cases are recurrent after tamoxifen therapy. This implies that the treatment of breast cancer is still hindered by resistance to tamoxifen. Recent studies have suggested that post-translational modifications of ERα play a significant role in endocrine resistance. The stability of both ERα protein and its transcriptome is regulated by a balance between E3 ubiquitin ligases and deubiquitinases. According to the current knowledge, approximately 100 deubiquitinases are encoded in the human genome, but it remains unclear which deubiquitinases play a critical role in estrogen signaling and endocrine resistance. Thus, decoding the key deubiquitinases that significantly impact estrogen signaling, including the control of ERα expression and stability, is critical for the improvement of breast cancer therapeutics.

We used several ER positive breast cancer cell lines, DUB siRNA library screening, xenograft models, endocrine-resistant (ERα-Y537S) model and performed immunoblotting, real time PCR, RNA sequencing, immunofluorescence, and luciferase activity assay to investigate the function of USP36 in breast cancer progression and tamoxifen resistance.

In this study, we identify Ubiquitin-specific peptidase 36 (USP36) as a key deubiquitinase involved in ERα signaling and the advancement of breast cancer by deubiquitinases siRNA library screening. In vitro and in vivo studies showed that USP36, but not its catalytically inactive mutant (C131A), could promote breast cancer progression through ERα signaling. Conversely, silencing USP36 inhibited tumorigenesis. In models resistant to endocrine therapy, silencing USP36 destabilized the resistant form of ERα (Y537S) and restored sensitivity to tamoxifen. Molecular studies indicated that USP36 inhibited K48-linked polyubiquitination of ERα and enhanced the ERα transcriptome. It is interesting to note that our results suggest USP36 as a novel biomarker for treatment of breast cancer.

Our study revealed the possibility that inhibiting USP36 combined with tamoxifen could provide a potential therapy for breast cancer.

The clinical studies for breast cancer (BC) are now assessing the efficacy of 2-Methoxyestradiol (2-ME), a naturally occurring derivative of estradiol. Our study aimed to explore the potential of combining the 2-ME and tamoxifen (TAM) on sensitization of TAM-resistant cells using LCC2 the TAM-resistant cells as a model and comparing the results to the sensitive cells MCF-7. Sulphorhodamine-B (SRB) assay is used to examine the 2-ME chemo-sensitizing impact on the cytotoxicity of TAM on LCC2 cells. Colorimetric assay kits were used to assess the level of the apoptosis-related markers caspases 3, Bcl2, and Bax in cell lysate. Hypoxia-inducible factor 1 alpha (HIF-1α) expression was measured using western blotting. Total cholesterol and triglyceride (TG) levels were examined colorimetrically, using the BIOLABO kit. The use of 2-ME enhanced the cytotoxic effects of TAM and effectively reversed TAM resistance. This was achieved by inhibiting the expression of HIF-1α, while concurrently increasing the levels of apoptotic marker caspase-3, as well as the pro-apoptotic protein Bax. Additionally, there was a reduction in the levels of Bcl2, an anti-apoptotic protein. Furthermore, a reduction in TG and cholesterol levels was noted. Our findings show that HIF-1α plays an important role in TAM resistance and that suppression of HIF-1α by 2-ME-mediated sensitization of BC-resistant cells to TAM. Therefore, the concurrent administration of TAM/2-ME might potentially serve as a viable therapeutic approach to address TAM resistance and enhance the overall therapy efficacy for patients with BC.

Estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer with ESR1 mutations presents a significant therapeutic challenge due to its adaptive resistance mechanisms to chemotherapy, especially endocrine treatment. Elacestrant, a novel oral selective estrogen receptor degrader (SERD), has emerged as a promising agent in this treatment-resistant era.

A comprehensive search was conducted on pivotal clinical trials, including the RAD1901-005 Trial, EMERALD TRIAL, ELIPSE, and ELEVATE, focusing on their methodologies, patient populations, treatment regimens, and outcomes.

This narrative review describes the available preclinical and clinical evidence on elacestrant, focusing on its pharmacodynamics, pharmacokinetics, efficacy, and safety within the existing literature. Elacestrant has demonstrated excellent activity against ESR1 mutations associated with resistance to first-line endocrine therapies. Clinical trials have shown improved progression-free survival in patients with advanced ER+/HER2-, ESR1-mutated breast cancer. Safety profiles indicate a tolerable side effect spectrum consistent with other agents. Its oral bioavailability offers a convenient alternative to injectable SERDs, with potential implications for patient adherence and quality of life. The review also discusses the comparative efficacy of elacestrant relative to existing endocrine therapies and its possible use in combination regimens.

Ongoing clinical trials assessing elacestrant and other SERDs will yield data that might aid clinicians in determining the optimal selection and order of endocrine treatment drugs for ER+ breast cancer. The integration of targeted and immunotherapeutic agents with traditional chemotherapy represents a pivotal shift in Breast Cancer treatment, moving towards more personalized and effective regimens.

All-trans retinoic acid (ATRA) has promising activity against breast cancer. However, the exact mechanisms of ATRA's anticancer effects remain complex and not fully understood. In this study, a network pharmacology and molecular docking approach was applied to identify key target genes related to ATRA's anti-breast cancer activity. Gene/disease enrichment analysis for predicted ATRA targets was performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID), the Comparative Toxicogenomics Database (CTD), and the Gene Set Cancer Analysis (GSCA) database. Protein-Protein Interaction Network (PPIN) generation and analysis was conducted via Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and cytoscape, respectively. Cancer-associated genes were evaluated using MyGeneVenn from the CTD. Differential expression analysis was conducted using the Tumor, Normal, and Metastatic (TNM) Plot tool and the Human Protein Atlas (HPA). The Glide docking program was used to predict ligand-protein binding. Treatment response predication and clinical profile assessment were performed using Receiver Operating Characteristic (ROC) Plotter and OncoDB databases, respectively. Cytotoxicity and gene expression were measured using MTT/fluorescent assays and Real-Time PCR, respectively. Molecular functions of ATRA targets (n = 209) included eicosanoid receptor activity and transcription factor activity. Some enriched pathways included inclusion body myositis and nuclear receptors pathways. Network analysis revealed 35 hub genes contributing to 3 modules, with 16 of them were associated with breast cancer. These genes were involved in apoptosis, cell cycle, androgen receptor pathway, and ESR-mediated signaling, among others. CCND1, ESR1, MMP9, MDM2, NCOA3, and RARA were significantly overexpressed in tumor samples. ATRA showed a high affinity towards CCND1/CDK4 and MMP9. CCND1, ESR1, and MDM2 were associated with poor treatment response and were downregulated after treatment of the breast cancer cell line with ATRA. CCND1 and ESR1 exhibited differential expression across breast cancer stages. Therefore, some part of ATRA's anti-breast cancer activity may be exerted through the CCND1/CDK4 complex.

GNA13 (Gα13) is one of two alpha subunit members of the G12/13 family of heterotrimeric G-proteins which mediate signaling downstream of GPCRs. It is known to be essential for embryonic development and vasculogenesis and has been increasingly shown to be involved in mediating several steps of cancer progression. Recent studies found that Gα13 can function as an oncogene and contributes to progression and metastasis of multiple tumor types, including ovarian, head and neck and prostate cancers. In most cases, Gα12 and Gα13, as closely related α-subunits in the subfamily, have similar cellular roles. However, in recent years their differences in signaling and function have started to emerge. We previously identified that Gα13 drives invasion of Triple Negative Breast Cancer (TNBC) cells in vitro. As a highly heterogenous disease with various well-defined molecular subtypes (ER+ /Her2-, ER+ /Her2+, Her2+, TNBC) and subtype associated outcomes, the function(s) of Gα13 beyond TNBC should be explored. Here, we report the finding that low expression of GNA13 is predictive of poorer survival in breast cancer, which challenges the conventional idea of Gα12/13 being universal oncogenes in solid tumors. Consistently, we found that Gα13 suppresses the proliferation in multiple ER+ breast cancer cell lines (MCF-7, ZR-75-1 and T47D). Loss of GNA13 expression drives cell proliferation, soft-agar colony formation and in vivo tumor formation in an orthotopic xenograft model. To evaluate the mechanism of Gα13 action, we performed RNA-sequencing analysis on these cell lines and found that loss of GNA13 results in the upregulation of MYC signaling pathways in ER+  breast cancer cells. Simultaneous silencing of MYC reversed the proliferative effect from the loss of GNA13, validating the role of MYC in Gα13 regulation of proliferation. Further, we found Gα13 regulates the expression of MYC, at both the transcript and protein level in an ERα dependent manner. Taken together, our study provides the first evidence for a tumor suppressive role for Gα13 in breast cancer cells and demonstrates for the first time the direct involvement of Gα13 in ER-dependent regulation of MYC signaling. With a few exceptions, elevated Gα13 levels are generally considered to be oncogenic, similar to Gα12. This study demonstrates an unexpected tumor suppressive role for Gα13 in ER+ breast cancer via regulation of MYC, suggesting that Gα13 can have subtype-dependent tumor suppressive roles in breast cancer.

Endocrine therapies targeting the estrogen receptor (ER/ESR1) are the cornerstone to treat ER-positive breast cancers patients, but resistance often limits their effectiveness. Understanding the molecular mechanisms is thus key to optimize the existing drugs and to develop new ER-modulators. Notable progress has been made although the fragmented way data is reported has reduced their potential impact. Here, we introduce EstroGene2.0, an expanded database of its precursor 1.0 version. EstroGene2.0 focusses on response and resistance to endocrine therapies in breast cancer models. Incorporating multi-omic profiling of 361 experiments from 212 studies across 28 cell lines, a user-friendly browser offers comprehensive data visualization and metadata mining capabilities (https://estrogeneii.web.app/). Taking advantage of the harmonized data collection, our follow-up meta-analysis revealed substantial diversity in response to different classes of ER-modulators including SERMs, SERDs, SERCA and LDD/PROTAC. Notably, endocrine resistant models exhibit a spectrum of transcriptomic alterations including a contra-directional shift in ER and interferon signaling, which is recapitulated clinically. Furthermore, dissecting multiple ESR1-mutant cell models revealed the different clinical relevance of genome-edited versus ectopic overexpression model engineering and identified high-confidence mutant-ER targets, such as NPY1R. These examples demonstrate how EstroGene2.0 helps investigate breast cancer's response to endocrine therapies and explore resistance mechanisms.

Breast cancer, particularly the estrogen receptor positive (ER+) subtype, remains a leading cause of cancer-related death among women. Endocrine therapy is the most effective treatment for ER+ breast cancer; however, the development of resistance presents a significant challenge. This study explored the role of the breast cancer antiestrogen resistance 4 (BCAR4) gene as a potential driver of resistance and a pivotal biomarker in breast cancer.

The researchers undertook a comprehensive analysis of 1743 patients spanning 6 independent cohorts. They examined the association of BCAR4 expression with patient outcomes across all breast cancer types and the PAM50 molecular subtypes. The relationship between elevated BCAR4 expression and resistance to endocrine therapy including AIs, the prevailing standard-of-care for endocrine therapy, was also investigated.

This meta-analysis corroborated the link between BCAR4 expression and adverse outcomes as well as resistance to endocrine therapy in breast cancer. Notably, BCAR4 expression is clinically significant in luminal A and B subtypes. Additionally, an association between BCAR4 expression and resistance to AI treatment was discerned.

This study expands on previous findings by demonstrating that BCAR4 expression is associated with resistance to newer therapies. The identification of patients with intrinsic resistance to hormone therapy is crucial to avoid ineffective treatment strategies. These findings contribute to our understanding of endocrine therapy resistance in breast cancer and could potentially guide the development of more effective treatment strategies.

Drug resistance presents a formidable challenge in the realm of breast cancer therapy. Accumulating evidence suggests that enhancer of zeste homolog 2 (EZH2), a component of the polycomb repressive complex 2 (PRC2), may serve as a key regulator in controlling drug resistance. EZH2 overexpression has been observed in breast cancer and many other malignancies, showing a strong correlation with poor outcomes. This review aims to summarize the mechanisms by which EZH2 regulates drug resistance, with a specific focus on breast cancer, in order to provide a comprehensive understanding of the underlying molecular processes. Additionally, we will discuss the current strategies and outcomes of targeting EZH2 using both single agents and combination therapies, with the goal of offering improved guidance for the clinical treatment of breast cancer patients who have developed drug resistance.

Background: Tamoxifen is commonly used in the treatment of hormonal-positive breast cancer. However, 30%-40% of tumors treated with tamoxifen develop resistance; therefore, an important step to overcome this resistance is to understand the underlying molecular and metabolic mechanisms. In the present work, we used metabolic profiling to determine potential biomarkers of tamoxifen resistance, and gene expression levels of enzymes important to these metabolites and then correlated the expression to the survival of patients receiving tamoxifen. Methods: Tamoxifen-resistant cell lines previously developed and characterized in our laboratory were metabolically profiled with nuclear magnetic resonance spectroscopy (NMR) using cryogenic probe, and the findings were correlated with the expression of genes that encode the key enzymes of the significant metabolites. Moreover, the effect of significantly altered genes on the overall survival of patients was assessed using the Kaplan-Meier plotter web tool. Results: We observed a significant increase in the levels of glutamine, taurine, glutathione, and xanthine, and a significant decrease in the branched-chain amino acids, valine, and isoleucine, as well as glutamate and cysteine in the tamoxifen-resistant cells compared to tamoxifen sensitive cells. Moreover, xanthine dehydrogenase and glutathione synthase gene expression were downregulated, whereas glucose-6-phosphate dehydrogenase was upregulated compared to control. Additionally, increased expression of xanthine dehydrogenase was associated with a better outcome for breast cancer patients. Conclusion: Overall, this study sheds light on metabolic pathways that are dysregulated in tamoxifen-resistant cell lines and the potential role of each of these pathways in the development of resistance.

Low-grade serous ovarian cancer (LGSOC) is a rare ovarian malignancy primarily affecting younger women and is characterized by an indolent growth pattern. It exhibits indolent growth and high estrogen/progesterone receptor expression, suggesting potential responsiveness to endocrine therapy. However, treatment efficacy remains limited due to the development of endocrine resistance. The mechanisms of resistance, whether primary or acquired, are still largely unknown and present a significant hurdle in achieving favorable treatment outcomes with endocrine therapy in these patients. In estrogen receptor-positive breast cancer, mechanisms of endocrine resistance have been largely explored and novel treatment strategies to overcome resistance have emerged. Considering the shared estrogen receptor positivity in LGSOC and breast cancer, we wanted to explore whether there are any parallel mechanisms of resistance and whether we can extend endocrine breast cancer treatments to LGSOC. This review aims to highlight the underlying molecular mechanisms possibly driving endocrine resistance in ovarian cancer, while also exploring the available therapeutic opportunities to overcome this resistance. By unraveling the potential pathways involved and examining emerging strategies, this review explores valuable insights for advancing treatment options and improving patient outcomes in LGSOC, which has limited therapeutic options available.

Other than for breast cancer, endocrine therapy has not been highly effective for gynecologic cancers. Endocrine therapy resistance in estrogen receptor positive gynecologic cancers is still poorly understood. In this retrospective study, we examined the estrogen receptor (ER) signaling pathway activities of breast, ovarian, endometrial, and cervical cancers to identify those that may predict endocrine therapy responsiveness.

Clinical and genomic data of women with breast and gynecological cancers were downloaded from cBioPortal for Cancer Genomics. Estrogen receptor alpha (ESR1) expression level and sample-level pathway enrichment scores (EERES) were calculated to classify patients into four groups (low/high ESR1 and low/high EERES). Correlation between ESR1/EERES score and survival was further validated with RNAseq data from low-grade serous ovarian cancer. Pathway analyses were performed among different ESR1/EERES groups to identify genes that correlate with endocrine resistance, which are validated using Cancer Cell Line Encyclopedia gene expression and Genomics of Drug Sensitivity in Cancer data.

We identified a novel combined prognostic value of ESR1 expression and the corresponding estrogen response signaling (EERES score) for breast cancer. The combined prognostic value (ESR1/EERES) may be applicable to other gynecologic cancers. More importantly, we discovered that ER signaling can cross-regulate MEK pathway activation. We identified downstream genes in the MEK pathway (EPHA2, INAVA, MALL, MPZL2, PCDH1, and TNFRSF21) that are potential endocrine therapy response biomarkers.

This study demonstrated that targeting both the ER and the ER signaling activity related MEK pathway may aid the development of endocrine therapy strategies for personalized medicine.

Estrogen receptor positive (ER+) breast cancer is the most common breast cancer diagnosed annually in the US with endocrine-based therapy as standard-of-care for this breast cancer subtype. Endocrine therapy includes treatment with antiestrogens, such as selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators (SERDs), and aromatase inhibitors (AIs). Despite the appreciable remission achievable with these treatments, a substantial cohort of women will experience primary tumor recurrence, subsequent metastasis, and eventual death due to their disease. In these cases, the breast cancer cells have become resistant to endocrine therapy, with endocrine resistance identified as the major obstacle to the medical oncologist and patient. To combat the development of endocrine resistance, the treatment options for ER+, HER2 negative breast cancer now include CDK4/6 inhibitors used as adjuvants to antiestrogen treatment. In addition to the dysregulated activity of CDK4/6, a plethora of genetic and biochemical mechanisms have been identified that contribute to endocrine resistance. These mechanisms, which have been identified by lab-based studies utilizing appropriate cell and animal models of breast cancer, and by clinical studies in which gene expression profiles identify candidate endocrine resistance genes, are the subject of this review. In addition, we will discuss molecular targeting strategies now utilized in conjunction with endocrine therapy to combat the development of resistance or target resistant breast cancer cells. Of approaches currently being explored to improve endocrine treatment efficacy and patient outcome, two adaptive cell survival mechanisms, autophagy, and "reversible" senescence, are considered molecular targets. Autophagy and/or senescence induction have been identified in response to most antiestrogen treatments currently being used for the treatment of ER+ breast cancer and are often induced in response to CDK4/6 inhibitors. Unfortunately, effective strategies to target these cell survival pathways have not yet been successfully developed. Thus, there is an urgent need for the continued interrogation of autophagy and "reversible" senescence in clinically relevant breast cancer models with the long-term goal of identifying new molecular targets for improved treatment of ER+ breast cancer.

The estrogen receptor-positive (ER+) breast cancer (BC), which constitutes the majority of BC cases, exhibits highly heterogeneous clinical behavior. To aid precision treatments, we aimed to find molecular subtypes of ER+ BC representing the tumor microenvironment and prognosis.

We analyzed RNA-seq data of 113 patients with BC and classified them according to the PAM50 intrinsic subtypes using gene expression profiles. Among them, we further focused on 44 patients with luminal-type (ER+) BC for subclassification. The Cancer Genome Atlas (TCGA) data of patients with BC were used as a validation data set to verify the new classification. We estimated the immune cell composition using CIBERSORT and further analyzed its association with clinical or molecular parameters.

Principal component analysis clearly divided the patients into two subgroups separately from the luminal A and B classification. The top differentially expressed genes between the subgroups were distinctly characterized by immunoglobulin and B-cell-related genes. We could also cluster a separate cohort of patients with luminal-type BC from TCGA into two subgroups on the basis of the expression of a B-cell-specific gene set, and patients who were predicted to have high B-cell immune activity had better prognoses than other patients.

Our transcriptomic approach emphasize a molecular phenotype of B-cell immunity in ER+ BC that may help to predict disease prognosis. Although further researches are required, B-cell immunity for patients with ER+ BC may be helpful for identifying patients who are good responders to chemotherapy or immunotherapy.

Chen et al explored clinicopathological features and prognostic factors, revealing advanced tumor stage, lung metastases, HER-2 overexpression, and triple-negative status as key contributors. Recent research connects astrocytes' role in brain metastasis with signaling pathways and the impact of Trastuzumab on HER-2 tumor survival. Factors such as positive HER2 status, lack of estrogen receptor expression, and liver metastasis are identified as additional risk factors. The routine use of magnetic resonance imaging, insights into gene mutations associated with metastasis, and the role of radiotherapy, including prophylaxis possibilities, is controversial in clinical practice. Understanding these risk factors in a multidisciplinary collaboration is precise for local treatments and targeted therapies, particularly for HER2+ tumors, impacting directly on longer survival.

Seventy percent of newly diagnosed breast cancers are estrogen receptor-α positive and HER2/neu negative [1]. First-line treatments incorporate endocrine therapy and cyclin-dependent kinase 4/6 inhibitors [2]. However, therapy resistance occurs in most patients [3-5]. Hence, there is an urgent need for effective second-line treatments. We previously showed that the potent estrogen receptor-β agonists, OSU-ERb-12 and LY500307, synergized with the selective estrogen receptor modulator, tamoxifen, in vitro. Furthermore, we showed that these compounds inhibited endocrine-resistant and cyclin-dependent kinase 4/6-inhibitor-resistant estrogen receptor α-positive cell lines in vitro [6]. Here, we used fulvestrant- and abemaciclib-resistant T47D-derived cell line xenografts to determine the efficacy of the combination of OSU-ERb-12 and LY500307 with tamoxifen in vivo.

Despite efficacy in vitro, treatments failed to reduce xenograft tumor volumes. Hence, we conclude that this treatment strategy lacks direct cancer cell-intrinsic cytotoxic efficacy in vivo.

Breast cancer subtypes expressing hormone receptors (HR+ BCa) have a good prognosis and respond to first-line endocrine therapy (ET). However, the majority of HR+ BCa patients exhibit intrinsic or acquired ET resistance (ET-R) and rapid onset of incurable metastatic BCa. With the failure of conventional ET, limited targeted therapy exists for ET-R HR+ BCa patients. The androgen receptor (AR) in HR-negative BCa subtypes is emerging as an attractive alternative target for therapy. The AR drives Luminal AR (LAR) triple-negative breast cancer progression, and LAR patients consistently exhibit positive clinical benefits with AR antagonists in clinical trials. In contrast, the function of the AR in HR+ BCa is more conflicting. AR in HR+ BCa correlates with a favorable prognosis, and yet, the AR supports the development of ET-R BCa. While AR antagonists were ineffective, ongoing clinical trials with a selective AR modulator have shown promise for HR+ BCa patients. To understand the incongruent actions of ARs in HR+ BCa, the current review discusses how the structure and post-translational modification impact AR function. Additionally, completed and ongoing clinical trials with FDA-approved AR-targeting agents for BCa are presented. Finally, we identify promising investigational small molecules and chimera drugs for future HR+ BCa therapy.

The role of estrogen receptors (ERs) in breast cancer is of great importance in both clinical practice and scientific exploration. However, around 15-30% of those affected do not see benefits from the usual treatments owing to the innate resistance mechanisms, while 30-40% will gain resistance through treatments. In order to address this problem and facilitate community-wide efforts, machine learning (ML)-based approaches are considered one of the most cost-effective and large-scale identification methods. Herein, we propose a new SMILES-based stacked approach, termed StackER, for the accelerated and efficient identification of ERα and ERβ inhibitors. In StackER, we first established an up-to-date dataset consisting of 1,996 and 1,207 compounds for ERα and ERβ, respectively. Using the up-to-date dataset, StackER explored a wide range of different SMILES-based feature descriptors and ML algorithms in order to generate probabilistic features (PFs). Finally, the selected PFs derived from the two-step feature selection strategy were used for the development of an efficient stacked model. Both cross-validation and independent tests showed that StackER surpassed several conventional ML classifiers and the existing method in precisely predicting ERα and ERβ inhibitors. Remarkably, StackER achieved MCC values of 0.829-0.847 and 0.712-0.786 in terms of the cross-validation and independent tests, respectively, which were 5.92-8.29 and 1.59-3.45% higher than the existing method. In addition, StackER was applied to determine useful features for being ERα and ERβ inhibitors and identify FDA-approved drugs as potential ERα inhibitors in efforts to facilitate drug repurposing. This innovative stacked method is anticipated to facilitate community-wide efforts in efficiently narrowing down ER inhibitor screening.

The constitutively active ESR1 Y537S mutation is associated with endocrine therapy (ET) resistance and progression of metastatic breast cancer through its effects on estrogen receptor (ERα) gene regulatory functions. However, the complex relationship between ERα and the progesterone receptor (PR), known as ERα/PR crosstalk, has yet to be characterized in the context of the ERα Y537S mutation. Using proximity ligation assays, we identify an increased physical interaction of ERα and PR in the context of the ERα Y537S mutation, including in the nucleus where this interaction may translate to altered gene expression. As such, more than 30 genes were differentially expressed in both patient tumor and cell line data (MCF7 and/or T47D cells) in the context of the ERα Y537S mutation compared to ERα WT. Of these, IRS1 stood out as a gene of interest, and ERα and PR occupancy at chromatin binding sites along IRS1 were uniquely altered in the context of ERα Y537S. Furthermore, siRNA knockdown of IRS1 or treatment with the IRS1 inhibitor NT-157 had a significant anti-proliferative effect in ERα Y537S cell lines, implicating IRS1 as a potential therapeutic target for restoring treatment sensitivity to patients with breast cancers harboring ERα Y537S mutations.

The predominant forms of breast cancer (BC) are hormone receptor-positive (HR+) tumors characterized by the expression of estrogen receptors (ERs) and/or progesterone receptors (PRs). Patients with HR+ tumors can benefit from endocrine therapy (ET). Three types of ET are approved for the treatment of HR+ BCs and include selective ER modulators, aromatase inhibitors, and selective ER downregulators. ET is the mainstay of adjuvant treatment in the early setting and the backbone of the first-line treatment in an advanced setting; however, the emergence of acquired resistance can lead to cancer recurrence or progression. The mechanisms of ET resistance are often related to the occurrence of mutations in the ESR1 gene, which encodes the ER-alpha protein. As ESR1 mutations are hardly detectable at diagnosis but are present in 30% to 40% of advanced BC (ABC) after treatment, the timeline of testing is crucial. To manage this resistance, ESR1 testing has recently been recommended; in ER+ HER2- ABC and circulating cell-free DNA, so-called liquid biopsy appears to be the most convenient way to detect the emergence of ESR1 mutations. Technically, several options exist, including Next Generation Sequencing and ultra-sensitive PCR-based techniques. In this context, personalization of ET through the surveillance of ESR1 mutations in the plasma of HR+ BC patients throughout the disease course represents an innovative way to improve the standard of care.

Lipid metabolism may be involved in the development of endocrine drug resistance in ER-positive (ER+) breast cancer (BC). This study aimed to investigate the relationship between serum lipid levels, risk stratification of dyslipidemia, and endocrine resistance. We collected the data from 166 ER + breast cancer patients who received endocrine therapy (ET). 73 of 166 patients (44.0%)developed endocrine resistance. Univariate and multivariate COX regression were conducted to explore the potential factors affecting endocrine resistance in BC. The clinical T stage, mean serum lipid levels in ET progression-free-survival (total cholesterol, triglycerides, low-density lipoprotein cholesterol, apolipoprotein A, and triglycerides/high-density lipoprotein cholesterol) were correlated with endocrine resistance (R = 0.214, P = .006; R = 0.268, P < .001; R = 0.182, P = .019;R = 0.197, P = .011; R = 0.211, P = .006; R = 0.159, P < .041). Clinical stage, triglycerides (TG) in endocrine therapy progression-free-survival (ePFS) and low-density lipoprotein cholesterol (LDL-C) in ePFS were independent predictors of endocrine resistance (P < .05; OR = 1.406, CI 1.108-1.783, P < .05; OR = 1.309, CI 1.026-1.669, P < .05, respectively). Moreover, in clinical stage III, the ePFS was worse in patients with in the high-risk and extremely high-risk group the median ePFS time was 8.0 months (95% CI: 1.140-14.860, P < .05). Clinical stage, TG in ePFS and LDL-C in ePFS may act as a new predictive biomarker for endocrine resistance in BC. The lipid levels of BC patients should be closely monitored throughout the treatment process, and patients with dyslipidemia should receive treatment immediately.

The majority of breast cancers are oestrogen receptor-positive (ER+). In ER+ cancers, oestrogen acts as a disease driver, so these tumours are likely to be susceptible to endocrine therapy (ET). ET works by blocking the hormone's synthesis or effect. A significant number of patients diagnosed with breast cancer will have the spread of tumour cells into regional lymph nodes either at the time of diagnosis, or as a recurrence some years later. Patients with node-positive disease have a poorer prognosis and can respond less well to ET. The nodal metastases may be genomically similar or, as is becoming more evident, may differ from the primary tumour. However, nodal metastatic disease is often not assessed, and treatment decisions are almost always based on biomarkers evaluated in the primary tumour. This review will summarise the evidence in the field on ER+, node-positive breast cancer, including diagnosis, treatment, prognosis and predictive tools.

Obesity and type 2 diabetes are chronic metabolic diseases that impact tens to hundreds of millions of adults, especially in developed countries. Each condition is associated with an elevated risk of breast cancer and with a poor prognosis after treatment. The mechanisms connecting poor metabolic health to breast cancer are numerous and include hyperinsulinemia, inflammation, excess nutrient availability, and adipose tissue dysfunction. Here, we focus on adipose tissue, highlighting important roles for both adipocytes and fibroblasts in breast cancer progression. One potentially important mediator of adipose tissue effects on breast cancer is the fibroblast growth factor receptor (FGFR) signaling network. Among the many roles of FGFR signaling, we postulate that key mechanisms driving aggressive breast cancer include epithelial-to-mesenchymal transition and cellular metabolic reprogramming. We also pose existing questions that may help better understand breast cancer biology in people with obesity, type 2 diabetes, and poor metabolic health.

In Switzerland, approximately 6000 new breast cancer cases and 1300 deaths are reported annually. Brain metastasis from breast cancer (BMBC) has a major effect on prognosis. This study aimed to identify prognostic factors for overall survival (OS) in a cohort of Swiss patients with BMBC. This study evaluated the prognosis on older BMBC, which has not been completely addressed in the literature.

We performed a retrospective chart review analysis with the primary endpoint of OS after a diagnosis of BMBC. The study population was divided into 2 groups based on an OS cut-off value of 12 months after diagnosis. Univariate and multivariate analyses of several risk factors, including age, were performed. To evaluate differences in OS according to age, we performed a secondary analysis to examine the prognostic value of clinical symptoms, metastatic pattern, and lymph node involvement in an older (≥65 years) vs. younger (<65 years) cohort.

From 1989 to 2019, 55 patients were identified as having BMBC, among whom 47 patients were confirmed to be dead. The median patient age was 58 years (range 25-83 years). Comorbidities were present in 45 (81.8%) patients. The median survival in the OS <12 and OS ≥12 months groups was 4.3 and 30.7 months, respectively (p<0.001). Multivariate analysis revealed no significant differences in terms of comorbidities, medication use, M-stage, and symptomatology between the 2 groups. Additionally, there was no significant difference in OS in the 2 subgroups of patients aged <65 and ≥65 years.

We concluded that age should not be a decisive factor in therapy planning for advanced breast cancer patients with BMBC.

Oxysterols play significant roles in many physiological and pathological processes including cancer. They modulate some of the cancer hallmarks pathways, influence the efficacy of anti-cancer drugs, and associate with patient survival. In this study, we aimed to analyze the role of 7-ketocholesterol (7-KC) in breast carcinoma cells and its potential modulation of the tamoxifen effect. 7-KC effects were studied in two estrogen receptor (ER)-positive (MCF-7 and T47D) and one ER-negative (BT-20) breast cancer cell lines. First, we tested the viability of cells in the presence of 7-KC. Next, we co-incubated cells with tamoxifen and sublethal concentrations of 7-KC. We also tested changes in caspase 3/7 activity, deregulation of the cell cycle, and changes in expression of selected genes/proteins in the presence of tamoxifen, 7-KC, or their combination. Finally, we analyzed the effect of 7-KC on cellular migration and invasion. We found that the presence of 7-KC slightly decreases the efficacy of tamoxifen in MCF-7 cells, while an increased effect of tamoxifen and higher caspase 3/7 activity was observed in the BT-20 cell line. In the T47D cell line, we did not find any modulation of tamoxifen efficacy by the presence of 7-KC. Expression analysis showed the deregulation in CYP1A1 and CYP1B1 with the opposite trend in MCF-7 and BT-20 cells. Moreover, 7-KC increased cellular migration and invasion potential regardless of the ER status. This study shows that 7-KC can modulate tamoxifen efficacy as well as cellular migration and invasion, making 7-KC a promising candidate for future studies.