Survival Of Breast Cancer Patients Research Articles

Mediator kinase inhibitors suppress triple-negative breast cancer growth and extend tumor suppression by mTOR and AKT inhibitors

Triple-negative breast cancers (TNBC) are treated primarily by chemotherapy and lack clinically validated therapeutic targets. In particular, inhibitors of the PI3K/AKT/mTOR pathway, abnormally activated in many breast cancers, failed to achieve clinical efficacy in TNBC due to the development of adaptive drug resistance, which is largely driven by the transcriptomic plasticity of TNBC. Expression of CDK8/19 Mediator kinases that control transcriptional reprogramming correlates with relapse-free survival and treatment failure in breast cancer patients, including TNBC. We now investigated how CDK8/19 inhibitors affect the growth of TNBC tumors and their response to mTOR and AKT inhibitors. In contrast to the effects of most anticancer drugs, all the tested human TNBC models (including patient-derived xenografts) responded to CDK8/19 inhibitors in vivo even when they did not respond in vitro. Furthermore, CDK8/19 inhibition extended the host survival of established lung metastases in a murine TNBC model, where the primary tumors were not significantly affected. CDK8/19 inhibitors synergized with an mTORC1 inhibitor everolimus and a pan-AKT inhibitor capivasertib in vitro and strongly potentiated these drugs in long-term in vivo studies. Transcriptomic analysis of tumors that responded or became adapted to everolimus revealed that drug adaptation in vivo was associated with major transcriptional changes in both tumor and stromal cells. Combining everolimus with a CDK8/19 inhibitor counteracted many of these changes and induced combination-specific effects on the expression of multiple genes that affect tumor growth. These results warrant the exploration of CDK8/19 Mediator kinase inhibitors as a new type of drugs for TNBC therapy.

FABP4-mediated lipid accumulation and lipolysis in tumor-associated macrophages promote breast cancer metastasis.

A high density of tumor-associated macrophages (TAMs) is associated with poorer prognosis and survival in breast cancer patients. Recent studies have shown that lipid accumulation in TAMs can promote tumor growth and metastasis in various models. However, the specific molecular mechanisms that drive lipid accumulation and tumor progression in TAMs remain largely unknown. Herein, we demonstrated that unsaturated fatty acids (FAs), unlike saturated ones, are more likely to form lipid droplets in murine macrophages. Specifically, unsaturated FAs, including linoleic acids (LA), activate the FABP4/CEBPα pathway, leading to triglyceride synthesis and lipid droplet formation. Furthermore, FABP4 enhances lipolysis and FA utilization by breast cancer cell lines, which promotes cancer cell migration in vitro and metastasis in vivo. Notably, a deficiency of FABP4 in murine macrophages significantly reduces LA-induced lipid metabolism. Therefore, our findings suggest FABP4 as a crucial lipid messenger that facilitates unsaturated FA-mediated lipid accumulation and lipolysis in TAMs, thus contributing to the metastasis of breast cancer.

FABP4-mediated lipid accumulation and lipolysis in tumor-associated macrophages promote breast cancer metastasis

A high density of tumor-associated macrophages (TAMs) is associated with poorer prognosis and survival in breast cancer patients. Recent studies have shown that lipid accumulation in TAMs can promote tumor growth and metastasis in various models. However, the specific molecular mechanisms that drive lipid accumulation and tumor progression in TAMs remain largely unknown. Herein, we demonstrated that unsaturated fatty acids (FAs), unlike saturated ones, are more likely to form lipid droplets in murine macrophages. Specifically, unsaturated FAs, including linoleic acids (LA), activate the FABP4/CEBPα pathway, leading to triglyceride synthesis and lipid droplet formation. Furthermore, FABP4 enhances lipolysis and FA utilization by breast cancer cell lines, which promotes cancer cell migration in vitro and metastasis in vivo. Notably, a deficiency of FABP4 in murine macrophages significantly reduces LA-induced lipid metabolism. Therefore, our findings suggest FABP4 as a crucial lipid messenger that facilitates unsaturated FA-mediated lipid accumulation and lipolysis in TAMs, thus contributing to the metastasis of breast cancer.

The association of preoperative serum free fatty acid levels with survival in breast cancer patients

Background and objectivesSerum free fatty acids (FFA) are associated with various types of cancer. However, the prognostic value of preoperative serum FFA levels and breast cancer (BC) remains unclear. This study aimed to elucidate the specific relationship between FFA levels and BC outcomes.MethodsA retrospective review was conducted on 4133 patients with BC admitted to Sun Yat-sen Memorial Hospital from January 2015 to October 2021. Preoperative serum FFA levels were detected by the enzymatic endpoint method. The relationship between serum FFA levels and clinical characteristics was analyzed based on FFA interquartile range. Restricted cubic splines and multivariate Cox regression analyses were used to assess the relationship between preoperative serum FFA levels and overall survival (OS) in patients with BC. The hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated.ResultsAccording to the FFA interquartile range, FFA levels were significantly correlated with OS (years) (p < 0.001). Restricted cubic spline analysis might reveal a U-shaped relationship between preoperative serum FFA levels and OS, after adjusting for other variables. According to the cutoff points for FFAs, multivariate Cox regression analyses showed that patients with low FFA levels (≤ 250 µmol/L) had higher rates of all-cause mortality and cancer-specific mortality than those with high FFA levels (530–700 µmol/L) in the total population and patients with a BMI of 18.5–24.0 kg/m2. A trend was observed indicating that elevated FFA levels (≥ 715 µmol/L) were associated with worse prognosis; however, this association failed to reach statistical significance.ConclusionsThere might be a nonlinear U-shaped relationship between preoperative serum FFA levels and survival in breast cancer patients, with lower FFA levels associated with worse OS. The effect of elevated FFA levels on prognosis requires further investigation.

Adipocytes reprogram the proteome of breast cancer cells in organotypic three-dimensional cell cultures.

While epidemiological evidence has long linked obesity with an increased risk of breast cancer, the intricate interactions between adipocytes and cancer cells within the tumor microenvironment remain largely uncharted territory. The use of organotypic three-dimensional (3D) cell cultures that more accurately mimic the spatial architecture of tumors represents an innovative approach to this complex issue. In the present study, we investigated the effects of adipocytes on the proteome of Hs578t breast cancer cells cultured in a 3D microenvironment. Using different treatments, we rigorously optimized the experimental conditions to induce the optimal differentiation of 3T3-L1 fibroblasts into mature adipocytes. Then, we grow the Hs578t cells in a simulated microenvironment using an on-top model for organotypic 3D cultures. Our data showed that cancer cells formed 3D stellate-like architectures when grown over an extracellular matrix proteins-enriched scaffold for 48h. Proteomic profiling using LC-MS/MS mass spectrometry of Hs578t cells grown in 3D conditions with or without the adipocyte-enriched culture discovered 916 unique proteins. Of these, 605 showed no significant changes in abundance, whereas 87 proteins were significantly upregulated and 224 downregulated after interaction with fat cells (p < 0.05, FC > 2.0). Bioinformatic analysis of upregulated proteins indicated that the most enriched GO terms and molecular functions were related to lipids transport, cell differentiation, hypoxia response, and cell junctions. In addition, several modulated proteins have been previously associated with breast cancer progression. Interestingly, lipid transport proteins, including PITPNM2, ATP2C1, ABCA12, HDLBP, and APOB, showed perturbations in their expression, which were also associated with low overall survival in breast cancer patients. Functional studies showed that the knockdown of apolipoprotein B (APOB) expression in Hs578t cells reduced the size of 3D cellular structures. Moreover, APOB-knocked cells cocultured with adipocytes for 48h exhibited a significant decrease of intracellular lipids, whereas an increase in the adipocytes was found. Our results indicate that the 3D microenvironment and the adipocytes crosstalk reprogram the proteome of breast cancer cells. These data help us understand the environmental effects in gene expression and contribute to discovering novel tumor proteins with potential intervention in breast cancer therapy.

Mediator Subunit Med4 Enforces Metastatic Dormancy in Breast Cancer.

Long term survival of breast cancer patients is limited due to recurrence from metastatic dormant cancer cells. However, the mechanisms by which these dormant breast cancer cells survive and awaken remain poorly understood. Our unbiased genome-scale genetic screen in mice identified Med4 as a novel cancer-cell intrinsic gatekeeper in metastatic reactivation. MED4 haploinsufficiency is prevalent in metastatic breast cancer patients and correlates with poorer prognosis. Syngeneic xenograft models revealed that Med4 enforces breast cancer dormancy. Contrary to the canonical function of the Mediator complex in activating gene expression, Med4 maintains 3D chromatin compaction and enhancer landscape, by preventing enhancer priming or activation through the suppression of H3K4me1 deposition. Med4 haploinsufficiency disrupts enhancer poise and reprograms the enhancer dynamics to facilitate extracellular matrix (ECM) gene expression and integrin-mediated mechano-transduction, driving metastatic growth. Our findings establish Med4 as a key regulator of cellular dormancy and a potential biomarker for high-risk metastatic relapse.

Identification of SLC31A1 as a prognostic biomarker and a target for therapeutics in breast cancer

Copper-induced cell death is regulated through protein lipoylation, which is critical for gene expression and phenotypic regulation. Neverless, the role of Cuproptosis-related genes in breast cancer (BC) remains unknown. This study aimed to construct a prognostic signature based on the expression of Cuproptosis-related genes in order to guide the diagnosis and treatment for BC. Cuproptosis-related genes prognostic signature has ata of 1250 BC tissues and 583 normal breast tissues were obtained from The Cancer Genome Atlas (TCGA), Genotype Tissue Expression (GTEx), and GEO GSE65212. The prognostic signature was established and evaluated with nineteen Cuproptosis-related genes. A series of in silico analyses based on SLC31A1, included expression analysis, independent prognostic analysis, correlation analysis, immune-related analysis and survival analysis. Finally, a series of cell experiments (including quantitative real-time polymerase chain reaction and western blot), and mice experiments were applied to evaluate the impact of SLC31A1 on BC. Cuproptosis-related genes prognostic signature has good predictive promising for survival in BC patients. We discovered that SLC31A1SLC31A1 was overexpressed in BC and was its independent prognostic factor. High expression of the SLC31A1 was correlated with poor prognosis and immune infiltrating of BC. SLC31A1 expression is associated with immune, chemotherapeutic and targeted therapy outcomes in BC. The proliferation, migration, and invasiveness of Her2 + enriched BC cells were decreased by SLC31A1 knockdown, also resulting in a decrease in tumor volume in mouse model. SLC31A1 is a candidate biomarker or therapeutic target in precision oncology, with diagnostic and prognostic significance in BC.

Effects of Differentially Methylated CpG Sites in Enhancer and Promoter Regions on the Chromatin Structures of Target LncRNAs in Breast Cancer.

Aberrant DNA methylation plays a crucial role in breast cancer progression by regulating gene expression. However, the regulatory pattern of DNA methylation in long noncoding RNAs (lncRNAs) for breast cancer remains unclear. In this study, we integrated gene expression, DNA methylation, and clinical data from breast cancer patients included in The Cancer Genome Atlas (TCGA) database. We examined DNA methylation distribution across various lncRNA categories, revealing distinct methylation characteristics. Through genome-wide correlation analysis, we identified the CpG sites located in lncRNAs and the distally associated CpG sites of lncRNAs. Functional genome enrichment analysis, conducted through the integration of ENCODE ChIP-seq data, revealed that differentially methylated CpG sites (DMCs) in lncRNAs were mostly located in promoter regions, while distally associated DMCs primarily acted on enhancer regions. By integrating Hi-C data, we found that DMCs in enhancer and promoter regions were closely associated with the changes in three-dimensional chromatin structures by affecting the formation of enhancer-promoter loops. Furthermore, through Cox regression analysis and three machine learning models, we identified 11 key methylation-driven lncRNAs (DIO3OS, ELOVL2-AS1, MIAT, LINC00536, C9orf163, AC105398.1, LINC02178, MILIP, HID1-AS1, KCNH1-IT1, and TMEM220-AS1) that were associated with the survival of breast cancer patients and constructed a prognostic risk scoring model, which demonstrated strong prognostic performance. These findings enhance our understanding of DNA methylation's role in lncRNA regulation in breast cancer and provide potential biomarkers for diagnosis.

Prognostic significance of malignant pleural effusions in patients with advanced luminal B breast cancer

BackgroundThough the survival of breast cancer (BC) patients with malignant pleural effusion (MPE) has been studied, this has not been specifically studied in the luminal B subtype. Therefore, this study investigated the characteristics and survival of luminal B-BC patients presenting with MPE.MethodsWe retrospectively analyzed 141 patients diagnosed with postoperative advanced Luminal B breast cancer, including 54 cases with MPE and 87 cases without MPE at the Tianjin Cancer Hospital from January 2012 to January 2015. We assessed the clinical characteristics between the groups.ResultsThe mean age of all patients was 47 years, with no significant difference between the two groups. Altogether, 29 (33%), 24 (28%), 28 (32%), 45 (52%), and 10 (11%) patients had lung, liver, bone, lymph node, and chest wall metastases, respectively. In addition. The difference in overall survival between the two groups was not significant (P>0.05). However, cox regression analysis showed that only the tumor clinical stage at initial diagnosis was related to short overall survival. Further, we conducted a subgroup analysis and found that the higher the clinical stage at initial diagnosis in age < 50 years patients, the shorter the overall survival, while age > 50 years patients was not. (P < 0.05).ConclusionsThere was no difference in the overall survival between luminal B-BC patients with MPE and those without. Clinical stages at initial diagnosis were an independent prognostic factor for age < 50 years luminal B BC with MPE overall survival. Our results may help clinicians make positive decisions regarding personalized treatment of luminal B-BC with MPE.

Retrospective evaluation of adjuvant capecitabine dosing patterns in triple negative breast cancer.

The CREATE-X trial demonstrated that adjuvant capecitabine was effective in prolonging survival in high-risk triple-negative breast cancer (TNBC) patients. However, the recommended dose is generally not well tolerated by the US population. The goal of this study is to analyze dosing patterns in an ethnically diverse cohort to better characterize tolerability and inform future dosing guidelines. In our single-center retrospective study, we evaluated safety and tolerability in TNBC patients undergoing adjuvant capecitabine treatment. The primary endpoint, relative dose intensity (RDI) across eight cycles, was examined alongside subgroup analyses based on age, race, BMI, and initial dose. Secondary endpoints include capecitabine-related side effects and survival. 67 patients who completed adjuvant capecitabine at University of Chicago Medicine (UCM) between January 2017 and November 2022 were eligible. The mean RDI across eight cycles of treatment was 60.2% (95% CI: 0.554-0.650). When compared to the CREATE-X trial, the RDI in our population was significantly lower (0.602 vs. 0.787, p < 0.001). There was no statistically significant difference in average RDI across eight cycles for patients stratified by age, BMI, race, or initial starting dose. The most frequently reported adverse events were hand-foot syndrome (73%), diarrhea (27%), and fatigue (22%), consistent with prior studies. Our data demonstrates that a significant portion of patients have a lower tolerated dose of capecitabine in comparison to the recommended adjuvant dose. Acknowledging the limitations of our single-center analysis, RDI was not significantly affected by age, race, BMI, or initial starting dose.

Could macrocytosis predict survival In advanced breast cancer patients that were treated with CDK 4–6 inhibitors?

IntroductionCyclin Dependent Kinase (CDK) 4–6 inhibitors are the recommended first-line treatment option for hormone-positive metastatic breast cancer (MBC). They show their effects by causing cell cycle arrest in G1-S phase. Neutropenia is the most common haematological side effect. In the literature, data on the association between CDK 4–6 inhibitors and macrocytosis are limited. We aimed to investigate the effect of macrocytosis on survival. MethodsWe retrospectively analysed 133 patients with de novo hormone positive MBC using CDK 4–6 inhibitors in first line treatment. Mean Corpuscular Volume (MCV) > 100 was considered macrocytosis and patients were divided into two groups; MCV<100 and MCV >100. The association of macrocytosis with clinicopathological features, Progression Free Survival (PFS) and Overall Survival (OS) were evaluated. Results42 patients were receiving palbociclib and 81 patients were receiving ribociclib. Median OS was determined as 33 months and median PFS was determined as 22 months. Macrocytosis ever rate was 45.8 % during follow-up. Macrocytosis was observed in 4.2 % of the patients in the first month, 16.7 % in the third month, 41.6 % in the sixth month and 42.2 % in the twelfth month. ER receptor level, ki-67, macrocytosis at 6–12 months and macrocytosis-ever which were found to affect OS as a result of univariate Cox regression analysis, were evaluated with multivariate Cox regression models and it was observed that they had significant effect on PFS and OS. ConclusionMacrocytosis may be a useful biomarker for the prediction of PFS and OS in MBC patients receiving CDK 4–6 inhibitors.

The prognostic value of skeletal muscle mass and density in breast cancer: a systematic review and meta-analysis.

Aim: The effect of skeletal muscle mass and density on the long-term survival outcome of breast cancer patients is unclear.Materials & methods: Systematically searched all articles in PubMed, Web of science, Springerlink, EMBASEand Wiley databases that studied the association between skeletal muscle and survival outcomes of breast cancer by 25September 2023. The hazard ratios and confidence intervals of the multiple factor analysis results controlling for confounding variables in the study were collected and analyzed using STATA 14.0 software.Results: This meta-analysis included a total of 13 studies, with a median age of 48.2years. Meta results showed that the survival (hazard ratio [HR]: 0.98, 95% CI: 0.89-1.08) and recurrence (HR: 0.96, 95% CI: 0.92-1.00) outcomes of breast cancer patients with sarcopenia were not significantly affected compared with those without sarcopenia. No significant heterogeneity or publication bias was observed in the study.Conclusion: The conclusion that skeletal muscle is regarded as a useful factor that can guide and optimize the prognosis of breast cancer patients is uncertain, or the result is very weak. Considering the impact of research quality and confounding factors, prospective studies are needed in the future to further demonstrate.PROSPERO identifier: CRD42023463480 (www.crd.york.ac.uk/prospero).

Conditional probabilistic diffusion model driven synthetic radiogenomic applications in breast cancer.

This study addresses the heterogeneity of Breast Cancer (BC) by employing a Conditional Probabilistic Diffusion Model (CPDM) to synthesize Magnetic Resonance Images (MRIs) based on multi-omic data, including gene expression, copy number variation, and DNA methylation. The lack of paired medical images and genomics data in previous studies presented a challenge, which the CPDM aims to overcome. The well-trained CPDM successfully generated synthetic MRIs for 726 TCGA-BRCA patients, who lacked actual MRIs, using their multi-omic profiles. Evaluation metrics such as Frechet's Inception Distance (FID), Mean Square Error (MSE), and Structural Similarity Index Measure (SSIM) demonstrated the CPDM's effectiveness, with an FID of 2.02, an MSE of 0.02, and an SSIM of 0.59 based on the 15-fold cross-validation. The synthetic MRIs were used to predict clinical attributes, achieving an Area Under the Receiver-Operating-Characteristic curve (AUROC) of 0.82 and an Area Under the Precision-Recall Curve (AUPRC) of 0.84 for predicting ER+/HER2+ subtypes. Additionally, the MRIs served to accurately predicted BC patient survival with a Concordance-index (C-index) score of 0.88, outperforming other baseline models. This research demonstrates the potential of CPDMs in generating MRIs based on BC patients' genomic profiles, offering valuable insights for radiogenomic research and advancements in precision medicine. The study provides a novel approach to understanding BC heterogeneity for early detection and personalized treatment.

9304 Integration of Glucocorticoid and Mineralocorticoid Receptor Signaling in Triple-negative Breast Cancer Models

Abstract Disclosure: S. Posani: None. C.A. Lange: None. Glucocorticoid receptors (GR) sense a convergence of host and cellular stress signaling to orchestrate an array of advanced cancer phenotypes associated with triple-negative breast cancer (TNBC) progression. The Lange lab reported p38 MAP kinase mediated phosphorylation of GR at serine 134 (Ser134) in response to tumor microenvironment-derived cytokines, such as TGF-beta-1. Phospho-Ser134-GR (p-Ser134-GR) upregulated gene sets that promote cancer cell survival, chemoresistance, altered metabolism, and migratory/invasive behavior in TNBC models. In addition to acting as ligands for GR, glucocorticoids also bind to and activate another closely related steroid hormone receptor - the mineralocorticoid receptor (MR). The elucidation of functional responses upon activation of MR remains an untapped area in breast cancer research. Our probe into public datasets (METABRIC, and TCGA) demonstrated significantly higher expression of MR transcripts in TNBC relative to luminal breast cancer. High expression of MR predicted worse overall survival in ERα-negative breast cancer patients compared to the low expressing cohort. Silencing of MR was carried out by siRNA-mediated knockdown and treatment with spironolactone, a competitive MR antagonist. Interestingly, MR knockdown significantly reduced the TGF-beta-1 induced migratory capacity of breast cancer cells compared to the wild-type control cells expressing endogenous MR. This biological phenotype of decreased TGF-beta-1 induced migration upon MR knockdown parallels the reduced migration we observed when the p38 MAPK site (Ser134 on GR was mutated to Ala in TNBC models. We therefore hypothesized that MR and GR may cooperate under the influence stress signaling in response to growth factors and cytokines abundantly present in the tumor-microenvironment. Preliminary data suggest that cytoplasmic p-Ser134-GR/MR complexes associate upon TGF-beta-1 treatment, while GR and/or MR ligands stimulate the formation of nuclear GR/MR complexes. We are further investigating cytokine- and stress-signal mediated regulation of GR/MR complexes and their functional role in TNBC biology. The overarching goal of this study is to elucidate if MR is a required GR binding-partner and a potential therapeutic target in GR- and cytokine-driven metastatic TNBC processes. Presentation: 6/2/2024

7873 Integration Of Glucocorticoid And Mineralocorticoid Receptor Signaling In Triple-Negative Breast Cancer Models

Abstract Disclosure: S. Posani: None. C.A. Lange: None. Glucocorticoid receptors (GR) sense a convergence of host and cellular stress signaling to orchestrate an array of advanced cancer phenotypes associated with triple-negative breast cancer (TNBC) progression. The Lange lab reported p38 MAP kinase mediated phosphorylation of GR at serine 134 (Ser134) in response to tumor microenvironment-derived cytokines, such as TGF-beta-1. Phospho-Ser134-GR (p-Ser134-GR) upregulated gene sets that promote cancer cell survival, chemoresistance, altered metabolism, and migratory/invasive behavior in TNBC models. In addition to acting as ligands for GR, glucocorticoids also bind to and activate another closely related steroid hormone receptor - the mineralocorticoid receptor (MR). The elucidation of functional responses upon activation of MR remains an untapped area in breast cancer research. Our probe into public datasets (METABRIC, and TCGA) demonstrated significantly higher expression of MR transcripts in TNBC relative to luminal breast cancer. High expression of MR predicted worse overall survival in ERα-negative breast cancer patients compared to the low expressing cohort. Silencing of MR was carried out by siRNA-mediated knockdown and treatment with spironolactone, a competitive MR antagonist. Interestingly, MR knockdown significantly reduced the TGF-beta-1 induced migratory capacity of breast cancer cells compared to the wild-type control cells expressing endogenous MR. This biological phenotype of decreased TGF-beta-1 induced migration upon MR knockdown parallels the reduced migration we observed when the p38 MAPK site (Ser134 on GR was mutated to Ala in TNBC models. We therefore hypothesized that MR and GR may cooperate under the influence stress signaling in response to growth factors and cytokines abundantly present in the tumor-microenvironment. Preliminary data suggest that cytoplasmic p-Ser134-GR/MR complexes associate upon TGF-beta-1 treatment, while GR and/or MR ligands stimulate the formation of nuclear GR/MR complexes. We are further investigating cytokine- and stress-signal mediated regulation of GR/MR complexes and their functional role in TNBC biology. The overarching goal of this study is to elucidate if MR is a required GR binding-partner and a potential therapeutic target in GR- and cytokine-driven metastatic TNBC processes. Presentation: 6/2/2024

9304 Integration Of Glucocorticoid And Mineralocorticoid Receptor Signaling In Triple-Negative Breast Cancer Models

Abstract Disclosure: S. Posani: None. C.A. Lange: None. Glucocorticoid receptors (GR) sense a convergence of host and cellular stress signaling to orchestrate an array of advanced cancer phenotypes associated with triple-negative breast cancer (TNBC) progression. The Lange lab reported p38 MAP kinase mediated phosphorylation of GR at serine 134 (Ser134) in response to tumor microenvironment-derived cytokines, such as TGF-beta-1. Phospho-Ser134-GR (p-Ser134-GR) upregulated gene sets that promote cancer cell survival, chemoresistance, altered metabolism, and migratory/invasive behavior in TNBC models. In addition to acting as ligands for GR, glucocorticoids also bind to and activate another closely related steroid hormone receptor - the mineralocorticoid receptor (MR). The elucidation of functional responses upon activation of MR remains an untapped area in breast cancer research. Our probe into public datasets (METABRIC, and TCGA) demonstrated significantly higher expression of MR transcripts in TNBC relative to luminal breast cancer. High expression of MR predicted worse overall survival in ERα-negative breast cancer patients compared to the low expressing cohort. Silencing of MR was carried out by siRNA-mediated knockdown and treatment with spironolactone, a competitive MR antagonist. Interestingly, MR knockdown significantly reduced the TGF-beta-1 induced migratory capacity of breast cancer cells compared to the wild-type control cells expressing endogenous MR. This biological phenotype of decreased TGF-beta-1 induced migration upon MR knockdown parallels the reduced migration we observed when the p38 MAPK site (Ser134 on GR was mutated to Ala in TNBC models. We therefore hypothesized that MR and GR may cooperate under the influence stress signaling in response to growth factors and cytokines abundantly present in the tumor-microenvironment. Preliminary data suggest that cytoplasmic p-Ser134-GR/MR complexes associate upon TGF-beta-1 treatment, while GR and/or MR ligands stimulate the formation of nuclear GR/MR complexes. We are further investigating cytokine- and stress-signal mediated regulation of GR/MR complexes and their functional role in TNBC biology. The overarching goal of this study is to elucidate if MR is a required GR binding-partner and a potential therapeutic target in GR- and cytokine-driven metastatic TNBC processes. Presentation: 6/2/2024

Traditional Chinese Medicine Herbs for Breast Cancer Prevention and Survival: A Narrative Review of Epidemiological Studies from Taiwan.

This review aims to describe the association of integrating traditional Chinese medicine (TCM) herbs into conventional medicine (CM) in preventing breast cancer and improving survival rates among breast cancer patients of Taiwan. Of 7 relevant studies, spanning 2014-2023, 4 investigated breast cancer risk in women with menopausal symptoms and other comorbidities. All 4 reported that TCM herbal use was associated with lower risks of developing breast cancer. Three studies investigated survival in newly-diagnosed breast cancer patients receiving CM. All reported that adjunctive TCM users had lower mortality rates than CM-only patients. However, the heterogeneity of study designs, populations, and interventions may limit the generalizability and robustness of the findings. TCM herbs may promote breast cancer prevention and survival when used alongside CM. More rigorous observational research and clinical trials in specific patient populations are needed to guide clinical decision-making.

Development of a polygenic score predicting drug resistance and patient outcome in breast cancer

Gene expression profiles of hundreds of cancer cell-lines and the cell-lines’ response to drug treatment were analyzed to identify genes whose expression correlated with drug resistance. In the GDSC dataset of 809 cancer cell lines, expression of 36 genes were associated with drug resistance (increased IC50) to many anti-cancer drugs. This was validated in the CTRP dataset of 860 cell lines. A polygenic score derived from the correlation coefficients of the 36 genes in cancer cell lines, UAB36, predicted resistance of cell lines to Tamoxifen. Although the 36 genes were selected from cell line behaviors, UAB36 successfully predicted survival of breast cancer patients in three different cohorts of patients treated with Tamoxifen. UAB36 outperforms two existing predictive gene signatures and is a predictor of outcome of breast cancer patients independent of the known clinical co-variates that affect outcome. This approach should provide promising polygenic biomarkers for resistance in many cancer types against specific drugs.

Strategies for the treatment of hormone receptor-positive HER2-low breast cancer based on clinical practice: a round table discussion.

Human epidermal growth factor receptor 2 (HER2)-low breast cancer is a newly identified targetable subset of breast tumors, and its clinical characteristics and treatment strategies are controversial. The emergence of novel anti-HER2 antibody-drug conjugate (ADC) has brought promising approaches for HER2-low breast cancer treatment. Several clinical trials have validated the efficacy and safety of trastuzumab deruxtecan (T-Dxd) in HER2-low breast cancer at different treatment settings. The treatment timing, candidate identification, long-term management, and overcoming drug resistance are crucial questions to improve breast cancer patient survival. Here we present a clinical case of hormone receptor-positive (HR+) HER2-low breast cancer patient who experienced neoadjuvant chemotherapy, surgery, adjuvant, and first-line endocrine therapy with limited effectiveness. After the treatment failure of CDK4/6 inhibitors, the utilization of T-Dxd brought a long-term disease response and tolerable low toxicities. In this round table discussion, we summarized opinions and recommendations from breast cancer surgeons and oncologists on treatment strategies for this patient. The discussion mainly focused on the precise diagnosis of HER2-low breast cancer, treatment design at different disease status, regimens selection according to drug response, strategies consideration for overcoming drug resistance and the management of adverse events in long-term survival. These opinions would provide critical insights to improve HER2-low breast cancer treatment and offer valuable suggestions for clinical practice.

Prognostic value of PLEKHA4 and its correlation with tumor-infiltrating immune cells in breast cancer: a comprehensive study based on bioinformatics and clinical analysis validation.

Pleckstrin homology containing family A, number 4 (PLEKHA4) plays a role in a number of biological processes in human cells, including cell polarization, growth, and proliferation. However, the relationship between PLEKHA4 expression and survival in breast cancer (BC) remains unclear. The aim of this study is to investigate the potential of PLEKHA4 as a prognostic indicator in BC. We obtained gene expression profiles of BC and normal tissues from the Tumor Immune Estimation Resource (TIMER), UALCAN web. Immunohistochemistry (IHC) staining was performed to investigate the protein expression and prognostic value of PLEKHA4 in BC patients. The prognostic value was analyzed using Kaplan-Meier curve analysis and Cox regression analysis in R software after downloading The Cancer Genome Atlas (TCGA) databases. The correlations between PLEKHA4 and tumor immune infiltrates were investigated via gene set variation analysis (GSVA). Signaling pathways related to PLEKHA4 expression were identified by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Both bioinformatics and IHC results showed that PLEKHA4 was expressed at low levels in BC tissues compared with the adjacent tissues. Furthermore, the expression of PLEKHA4 was negatively correlated with ages (χ2=6.394, P=0.01), molecular subtype (χ2=15.606, P=0.001), lymph node metastasis (χ2=13.753, P=0.004), tumor-node-metastasis (TNM) stage (χ2=22.616, P<0.001). Kaplan-Meier curves implicated low expression of PLEKHA4 was associated with worse survival of BC patients [hazard ratio (HR) =0.46, P=0.01]. Cox regression models showed that low PLEKHA4 expression could be an independent risk factor for BC (HR =0.911, P=0.006). The results of gene set enrichment analysis (GSEA) showed that cell cycle, Notch signaling pathway, nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway, and Rho GTPases were highly enriched in the low PLEKHA4 expression group, as identified by GO and KEGG. Additionally, in BC, PLEKHA4 expression displayed a positive correlation with the infiltration of natural killer (NK) cells (P<0.001), CD8+ T cells (P<0.001), B cells (P<0.001), neutrophils (P<0.001), and dendritic cells (DCs) (P<0.001). The findings indicate that PLEKHA4 is an independent prognostic biomarker associated with key signaling pathways and immune infiltration in BC. Targeting PLEKHA4 may contribute to improving immunotherapy for BC.