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Mutation study for high-risk breast and ovarian cancer (HBOC) has been extensively studied in patients of different ethnicities. Here we compared the germline mutation rate and mutation spectrum of patients (n = 4341) with benign breast diseases or breast cancers, with and without other risk factors. Three cohorts of Chinese patients were recruited. The first cohort, high-risk cohort (HR, n = 3935) included high-risk breast cancer patients fulfilling high-risk HBOC criteria and who are recruited at our genetics clinic. The second cohort, unselected cancer cohort (CC, n = 307) was from general recruitment of patients with breast cancer at breast surgery clinics. The third cohort, benign breast lesion cohort (NC, n = 99) comprised 99 patients with benign breast diseases such as fibroadenoma, fibroadenomatoid hyperplasia, and intraductal papilloma. Thirty HBOC related genes were sequenced on the above-mentioned patient cohorts. The germline mutation rates of HR, CC, and NC cohort were 11.9%, 6.5%, and 8.1%, respectively. In the CC cohort, 29.3% (90/307) of patients fulfilled the National Comprehensive Cancer Network (NCCN) high-risk genetic test criteria 2022 v.2. The mutation rate for this group of patients was 11.1%, similar to that of the HR cohort, while the mutation rate for those not fulfilling testing criteria was 4.6%, like that of the NC cohort. High penetrance genes (BRCA1/2, CDH1, PALB2, PTEN, and TP53) mutations were only found in the HR (10.6%) and CC (3.3%) cohorts but were not found in the NC cohort. ATM, BRIP1, RAD51C, and RAD51D mutations were identified in all cohorts. RAD51C and RAD51D mutations showed conflicting penetrance. An unexpectedly high mutation rate of total 2% was found in the NC cohort but it was only 0.3% and 0.5% in the HR cohort and CC cohort, respectively. Our results show a clinical need to enhance genetic testing of unselected breast cancer patients to identify the high-risk patients.
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Background Breast-conserving surgeries have significantly advanced breast cancer treatment, offering favorable oncological outcomes, enhanced cosmetic results, reduced postoperative morbidity, and better psychological acceptance compared to mastectomy. The introduction of neoadjuvant therapy has expanded the applicability of breast conservation surgery to include locally advanced tumors. Tumor response to neoadjuvant chemotherapy is evaluated using imaging modalities such as breast ultrasound, breast magnetic resonance imaging (MRI), and positron emission tomography/computed tomography (PET/CT). Accurate prediction of therapeutic response facilitates the planning of surgical and adjuvant treatments. This study aims to compare the diagnostic accuracy of MRI and PET/CT in predicting treatment response to neoadjuvant chemotherapy in breast cancer patients. Methods This retrospective study was conducted at a tertiary care center in Bahrain. A total of 138 patients with locally advanced breast cancer or human epidermal growth factor receptor-2 (HER2) positive, hormone receptor-negative cancers who underwent breast-conserving surgeries between June 2018 and December 2022 were included. The inclusion criteria focused on patients achieving a complete pathological response following neoadjuvant systemic therapy, ensuring a homogenous study population. Patients with hormone receptor-positive early breast cancers or metastatic tumors, ineligible for neoadjuvant chemotherapy, were excluded. Non-responders and partial responders were also excluded from the study. Statistical analysis was performed using IBM SPSS v26.0 (IBM Corp., Armonk, US). Response rates for the imaging modalities and histopathology results were assessed. Agreement between histology and imaging modalities was computed using kappa statistics. Diagnostic performance for predicting "no residual" disease was evaluated using the McNemar Test. All tests were two-tailed, with a p-value <0.05 considered statistically significant. Results The study included 138 patients, of whom 73 (52.9%) had an incomplete response or residual disease, while 65 (47.1%) had a complete response or no residual disease according to histology reports. There was slight agreement between post-neoadjuvant MRI and histology results (Cohen's kappa 0.172, p=0.010), while substantial agreement was observed between post-neoadjuvant PET/CT and histology results (Cohen's kappa 0.614, p=0.000). PET/CT demonstrated a higher sensitivity of 93.8% (p<0.001) and a specificity of 68.5%. Although MRI was more specific, the positive predictive value was comparable for both PET/CT and MRI. Conclusion PET/CT shows higher sensitivity and can serve as an early marker for predicting complete pathological response in post-neoadjuvant breast cancer patients. However, the prediction of residual disease is optimized by combining both MRI and PET/CT as diagnostic modalities.
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Breast cancer is a major public health concern worldwide, being the most commonly diagnosed cancer among women and a leading cause of cancer-related deaths. Recent studies have highlighted the significance of non-histone methylation in breast cancer, which modulates the activity, interaction, localization, and stability of target proteins. This regulation affects critical processes such as oncogenesis, tumor growth, proliferation, invasion, migration, and immune responses. This review delves into the enzymes responsible for non-histone methylation, such as protein arginine methyltransferases (PRMTs), lysine methyltransferases (KMTs), and demethylases, and explores their roles in breast cancer. By elucidating the molecular mechanisms and functional consequences of non-histone methylation, this review aims to provide insights into novel therapeutic strategies targeting these pathways. The therapeutic potential of targeting non-histone methylation to overcome drug resistance and enhance treatment efficacy in breast cancer is also discussed, highlighting promising avenues for future research and clinical applications.
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Multigene panels can analyze high and moderate/intermediate penetrance genes that predispose to breast cancer (BC), providing an opportunity to identify at-risk individuals within affected families. However, considering the complexity of different pathogenic variants and correlated clinical manifestations, a multidisciplinary team is needed to effectively manage BC. A classification of pathogenic variants included in multigene panels was presented in this narrative review to evaluate their clinical utility in BC. Clinical management was discussed for each category and focused on BC, including available evidence regarding the multidisciplinary and integrated management of patients with BC. The integration of both genetic testing and counseling is required for customized decisions in therapeutic strategies and preventative initiatives, as well as for a defined multidisciplinary approach, considering the continuous evolution of guidelines and research in the field.
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Neoplasias de la Mama , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/terapia , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/patología , Femenino , Pruebas Genéticas/métodos , Proteína BRCA2/genética , Proteína BRCA1/genética , Mutación , Manejo de la EnfermedadRESUMEN
OBJECTIVE: Estrogen receptor-positive (ER+) breast cancer represents about 80% of cases, tamoxifen is the election neoadjuvant chemotherapy. However, a large percentage of patients develop chemoresistance, compromising recovery. Clinical evidence suggests that high plasmatic levels of low-density lipoproteins (LDL) could promote cancer progression. The present study analyzed the effect of LDL on the primary plasmatic active Tamoxifen's metabolites resistance acquisition, 4-hydroxytamoxifen (4OH-Tam) and 4-hydroxy-N-desmethyl-tamoxifen (endoxifen), in breast cancer ERα + cells (MCF-7). METHODS: Two resistant cellular variants, MCF-7Var-H and MCF-7Var-I, were generated by a novel strategy and their phenotype features were evaluated. Phenotypic assessment was performed by MTT assays, cytometry, immunofluorescence microscopy, zymography and protein expression analysis. RESULTS: MCF-7Var-H, generated only with tamoxifen metabolites, showed a critical down-regulation in hormone receptors, augmented migration capacity, metalloprotease 9 extracellular medium excretion, and a mesenchymal morphology in contrast with native MCF-7, suggesting the transition towards Triple-negative breast cancer (TNBC) phenotype. In contrast, MCF-7Var-I which was generated in a high LDL media, showed only a slight upregulation in ER and other less noticeable metabolic adaptations. Results suggest a potential role of transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) in phenotypic differences observed among variants. CONCLUSION: LDL high or low concentrations during Tamoxifen´s metabolites chemoresistance acquisition leads to different cellular mechanisms related to chemoresistance. A novel adaptative cellular response associated with Nrf2 activity could be implicated.
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Resistencia a Antineoplásicos , Receptor alfa de Estrógeno , Lipoproteínas LDL , Fenotipo , Tamoxifeno , Neoplasias de la Mama Triple Negativas , Humanos , Tamoxifeno/farmacología , Tamoxifeno/análogos & derivados , Resistencia a Antineoplásicos/efectos de los fármacos , Células MCF-7 , Femenino , Receptor alfa de Estrógeno/metabolismo , Receptor alfa de Estrógeno/genética , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Lipoproteínas LDL/metabolismo , Antineoplásicos Hormonales/farmacología , Movimiento Celular/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacosRESUMEN
Double pathogenic mutations occurring in an individual are considered a rare event. The introduction of a multiple-gene panel at Hong Kong Hereditary Breast Cancer Family Registry has allowed the identification of pathogenic variants in multiple genes, providing more information on clinical management and surveillance to the proband and their family members. Breast cancer patients who are double heterozygous (DH) for different hereditary breast and ovarian cancer syndrome (HBCO)-related genes were identified from a cohort of 3649 Chinese patients. Nine patients (0.25%) were observed to have germline DH mutations in ATM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MSH6, PALB2, and TP53. Three probands were diagnosed with unilateral breast cancer, two patients were diagnosed with bilateral breast cancer, and four patients had multiple primary cancers. The median age for breast cancer diagnosis was an early age of 36 years. Chinese DH carriers did not show worse phenotypes or have a significantly downhill clinical presentation. However, seven out of nine (77.8%) of our DH carriers harbored a BRCA1 mutation, and four of them (44.4%) developed bilateral breast cancer, suggesting Chinese DH individuals may have a higher chance of having bilateral breast cancer than other populations (p = 0.0237).
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Breast cancers (BCs) are solid tumors composed of heterogeneous tissues consisting of cancer cells and an ever-changing tumor microenvironment (TME). The TME includes, among other non-cancer cell types, immune cells influencing the immune context of cancer tissues. In particular, the cross talk of immune cells and their interactions with cancer cells dramatically influence BC dissemination, immunoediting, and the outcomes of cancer therapies. Tumor-infiltrating lymphocytes (TILs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs) represent prominent immune cell populations of breast TMEs, and they have important roles in cancer immunoescape and dissemination. Therefore, in this article we review the features of TILs, TAMs, and MDSCs in BCs. Moreover, we highlight the mechanisms by which these immune cells remodel the immune TME and lead to breast cancer metastasis.
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Neoplasias de la Mama , Linfocitos Infiltrantes de Tumor , Células Supresoras de Origen Mieloide , Metástasis de la Neoplasia , Microambiente Tumoral , Macrófagos Asociados a Tumores , Humanos , Microambiente Tumoral/inmunología , Neoplasias de la Mama/patología , Neoplasias de la Mama/inmunología , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Células Supresoras de Origen Mieloide/patología , Femenino , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismo , Macrófagos Asociados a Tumores/patología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos T/inmunología , AnimalesRESUMEN
Tumor-associated macrophages (TAMs) is a key element in the breast tumor microenvironment. CD163 and CD206 have been utilized for TAM identification, but the clinical implications of TAMs identified by these markers have not been thoroughly explored. This study conducted a comparative analysis of CD163 and CD206 TAMs using digital image analysis, focusing on their spatial distribution and prognostic significance in relation to tumor-infiltrating lymphocytes (TILs). Distinct clinico-pathological and prognostic characteristics were noted between the two types of TAMs. CD163 TAMs were linked to high-grade tumors (p = 0.006), whereas CD206 TAMs were associated with a higher incidence of nodal metastasis (p = 0.033). CD206 TAMs were predominantly found in the stroma, with more cases being stromal CD206-high (sCD206-high) than tumoral CD206-high (tCD206-high) (p = 0.024). Regarding prognostication, patients stratified according to stromal and tumoral densities of CD163 showed different disease-free survival (DFS) time. Specifically, those that were sCD163-low but tCD163-high exhibited the poorest DFS (chi-square = 10.853, p = 0.013). Furthermore, a high sCD163-to-stromal-TILs ratio was identified as an independent predictor of unfavorable survival outcomes (DFS: HR = 3.477, p = 0.018). The spatial distribution and interactions with TILs enhanced the prognostic value of CD163 TAMs, while CD206 TAMs appeared to have limited prognostic utility in breast cancer cases.
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In addition to the major subcutaneous and visceral adipose tissues (AT), other adipose depots are dispersed throughout the body and are found in close interaction with proximal organs such as mammary and periprostatic AT (MAT and PPAT respectively). These ATs have an effect on proximal organ function during physiological processes and diseases such as cancer. We highlighted here some of their most distinctive features in terms of tissular organization and responses to external stimuli and discussed how obesity affects them based on our current knowledge.
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Tejido Adiposo , Obesidad , Humanos , Tejido Adiposo/fisiología , Femenino , Obesidad/fisiopatología , Neoplasias/patología , Animales , Mama/fisiología , Mama/patología , Neoplasias de la Mama/patología , Glándulas Mamarias Humanas/fisiología , Glándulas Mamarias Humanas/patología , Grasa Intraabdominal , Grasa Subcutánea/fisiología , Grasa Subcutánea/patologíaRESUMEN
BACKGROUND: Approximately 30% to 50% of patients with human epidermal growth factor receptor 2-positive metastatic breast cancer develop brain metastasis (BMs). Pyrotinib has shown promising efficacy in these patients. However, real-world evidence supporting its use is scarce. Therefore, we evaluate the efficacy and safety of pyrotinib-based regimens in the real world. MATERIALS AND METHODS: We enrolled patients with BMs from various healthcare facilities in China's Shandong region and used an updated breast-graded prognostic assessment (breast-GPA) to predict survival outcomes. RESULTS: Efficacy and toxicity were assessed in 101 patients. Overall, the median progression-free survival (PFS) was 11.0 months (95% CI, 7.6-14.4 months). PFS was shorter in patients with a breast-GPA of 0 to 2.0 (P< .001). Previous treatment with pertuzumab plus trastuzumab (P = .039) and varying numbers of BMs (P = .028) had a significant positive correlation with PFS. Additionally, radiotherapy (P = .033) for BMs, especially pyrotinib concurrent with radiotherapy (P = .013), significantly prolonged the PFS. In patients with a breast-GPA of 0 to 2.0, a significant difference in PFS was observed depending on whether the brain was the first metastatic site (P< .001). Furthermore, a breast-GPA (0-2.0 vs. 2.5-4.0), and radiotherapy for BMs were found to be independent predictors of PFS. Overall, the objective response rate was 42.6%, while the disease control rate was 88.1%. Diarrhea emerged as the most common adverse event. CONCLUSION: Pyrotinib-based therapy is effective and tolerable in human epidermal growth factor receptor 2-positive metastatic breast cancer with BMs. Patients who underwent radiotherapy for BMs, particularly those who received pyrotinib concurrently with radiotherapy, exhibited a more favorable prognosis.
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Aminoquinolinas , Neoplasias Encefálicas , Neoplasias de la Mama , Receptor ErbB-2 , Humanos , Femenino , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Persona de Mediana Edad , Receptor ErbB-2/metabolismo , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/tratamiento farmacológico , Adulto , Anciano , Aminoquinolinas/uso terapéutico , Aminoquinolinas/administración & dosificación , Acrilamidas/uso terapéutico , Acrilamidas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Supervivencia sin Progresión , Pronóstico , China/epidemiología , Resultado del Tratamiento , Estudios RetrospectivosRESUMEN
Background and Objectives: This study aimed to explore biomarker change after NAC (neoadjuvant chemotherapy) and to investigate biomarker expression as a prognostic factor in patients with residual disease (RD) after NAC. Materials and Methods: We retrospectively evaluated 104 patients with invasive breast cancer, who underwent NAC and surgery at Pusan National University Hospital from 2015 to July 2022. The expression of the biomarker was assessed, and the overall survival (OS) and disease-free survival (DFS) were investigated. Results: After NAC, 24 patients (23.1%) out of 104 total patients had a pathological complete response (pCR). We found that changes in at least one biomarker were observed in 41 patients (51.2%), among 80 patients with RD. In patients with RD after NAC (n = 80), a subtype change was identified in 20 patients (25.0%). Any kind of change in the HER2 status was present 19 (23.7%) patients. The hormone receptor (HR)+/HER2+ subtype was significantly associated with better disease-free survival (DFS) (HR, 0.13; 95% CI, 0.02-0.99; p = 0.049). No change in p53 was associated with better DFS, and negative-to-positive change in p53 expression after NAC was correlated with worse DFS (p < 0.001). Negative-to-positive change in p53 was an independent, worse DFS factor in the multivariate analysis (HR,18.44; 95% CI, 1.86-182.97; p = 0.013). Conclusions: Biomarker change and subtype change after NAC were not infrequent, which can affect the further treatment strategy after surgery. The expression change of p53 might have a prognostic role. Overall, we suggest that the re-evaluation of biomarkers after NAC can provide a prognostic role and is needed for the best decision to be made on further treatment.
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Biomarcadores de Tumor , Neoplasias de la Mama , Terapia Neoadyuvante , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Terapia Neoadyuvante/métodos , Persona de Mediana Edad , Estudios Retrospectivos , Adulto , Biomarcadores de Tumor/análisis , Anciano , Supervivencia sin Enfermedad , Quimioterapia Adyuvante/métodos , Pronóstico , Receptor ErbB-2/análisis , Análisis de SupervivenciaRESUMEN
Novel components in the noncanonical Hippo pathway that mediate the growth, metastasis, and drug resistance of breast cancer (BC) cells need to be identified. Here, we showed that expression of SAM and SH3 domain-containing protein 1 (SASH1) is negatively correlated with expression of mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) in a subpopulation of patients with luminal-subtype BC. Downregulated SASH1 and upregulated MAP4K4 synergistically regulated the proliferation, migration, and invasion of luminal-subtype BC cells. The expression of LATS2, SASH1, and YAP1 and the phosphorylation of YAP1 were negatively regulated by MAP4K4, and LATS2 then phosphorylated SASH1 to form a novel MAP4K4-LATS2-SASH1-YAP1 cascade. Dephosphorylation of Yes1 associated transcriptional regulator (YAP1), YAP1/TAZ nuclear translocation, and downstream transcriptional regulation of YAP1 were promoted by the combined effects of ectopic MAP4K4 expression and SASH1 silencing. Targeted inhibition of MAP4K4 blocked proliferation, cell migration, and ER signaling both in vitro and in vivo. Our findings reveal a novel MAP4K4-LATS2-SASH1-YAP1 phosphorylation cascade, a noncanonical Hippo pathway that mediates ER signaling, tumorigenesis, and metastasis in breast cancer. Targeted intervention with this noncanonical Hippo pathway may constitute a novel alternative therapeutic approach for endocrine-resistant BC.
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Proteínas Adaptadoras Transductoras de Señales , Neoplasias de la Mama , Péptidos y Proteínas de Señalización Intracelular , Proteínas Serina-Treonina Quinasas , Factores de Transcripción , Proteínas Supresoras de Tumor , Proteínas Señalizadoras YAP , Humanos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Femenino , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Señalizadoras YAP/metabolismo , Proteínas Señalizadoras YAP/genética , Proteínas Supresoras de Tumor/metabolismo , Proteínas Supresoras de Tumor/genética , Animales , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Fosfoproteínas/metabolismo , Fosfoproteínas/genética , Ratones , Transducción de Señal , Metástasis de la Neoplasia , Movimiento Celular , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/genética , Fosforilación , Ratones Desnudos , Carcinogénesis/genética , Carcinogénesis/metabolismoRESUMEN
Breast cancer is one of the most common cancers threatening women's health. Our previous study found that silibinin induced the death of MCF-7 and MDA-MB-231 human breast cancer cells. We noticed that silibinin-induced cell damage was accompanied by morphological changes, including the increased cell aspect ratio (cell length/width) and decreased cell area. Besides, the cytoskeleton is also destroyed in cells treated with silibinin. YAP/TAZ, a mechanical signal sensor interacted with extracellular pressure, cell adhesion area and cytoskeleton, is also closely associated with cell survival, proliferation and migration. Thus, the involvement of YAP/TAZ in the cytotoxicity of silibinin in breast cancer cells has attracted our interests. Excitingly, we find that silibinin inhibits the nuclear translocation of YAP/TAZ in MCF-7 and MDA-MB-231 cells, and reduces the mRNA expressions of YAP/TAZ target genes, ACVR1, MnSOD and ANKRD. More importantly, expression of YAP1 gene is negatively correlated with the survival of the patients with breast cancers. Molecular docking analysis reveals high probabilities for binding of silibinin to the proteins in the YAP pathways. DARTS and CETSA results confirm the binding abilities of silibinin to YAP and LATS. Inhibiting YAP pathway either by addition of verteporfin, an inhibitor of YAP/TAZ-TEAD, or by transfection of si-RNAs targeting YAP or TAZ further enhances silibinin-induced cell damage. While enhancing YAP activity by silencing LATS1/2 or overexpressing YAPS127/397A, an active form of YAP, attenuates silibinin-induced cell damage. These findings demonstrate that inhibition of the YAP/TAZ pathway contributes to cytotoxicity of silibinin in breast cancers, shedding lights on YAP/TAZ-targeted cancer therapies.
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Neoplasias de la Mama , Silibina , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , Proteínas Señalizadoras YAP , Femenino , Humanos , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Células MCF-7 , Simulación del Acoplamiento Molecular , Fosfoproteínas/metabolismo , Transducción de Señal/efectos de los fármacos , Silibina/farmacología , Transactivadores/metabolismo , Factores de Transcripción/metabolismo , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ/antagonistas & inhibidores , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ/efectos de los fármacos , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ/metabolismo , Verteporfina/farmacología , Proteínas Señalizadoras YAP/antagonistas & inhibidores , Proteínas Señalizadoras YAP/efectos de los fármacos , Proteínas Señalizadoras YAP/metabolismoRESUMEN
BACKGROUND: Triple-negative breast cancer (TNBC) subtyping by gene profiling has provided valuable clinical information. Here, we aimed to evaluate the relevance of TNBC subtyping using immunohistochemistry (IHC), which could be a more clinically practical approach, for prognostication and applications in patient management. METHODS: A total of 123 TNBC cases were classified using androgen receptor (AR), CD8, Forkhead box C1 protein (FOXC1), and doublecortin-like kinase 1 (DCLK1) into luminal androgen receptor (LAR), basal-like immunosuppressive (BLIS), mesenchymal-like (MES), and immunomodulatory (IM) subtypes. The IM cases were further divided into the IM-excluded and IM-inflamed categories by CD8 spatial distribution. Their clinicopathological and biomarker profiles and prognoses were evaluated. RESULTS: LAR (28.6%) and MES (11.2%) were the most and least frequent subtypes. The IHC-TNBC subtypes demonstrated distinct clinicopathological features and biomarker profiles, corresponding to the reported features in gene profiling studies. IM-inflamed subtype had the best outcome, while BLIS had a significantly poorer survival. Differential breast-specific marker expressions were found. Trichorhinophalangeal syndrome type 1 (TRPS1) was more sensitive for IM-inflamed and BLIS, GATA-binding protein 3 (GATA3) for IM-excluded and MES, and gross cystic disease fluid protein 15 (GCDFP15) for LAR subtypes. CONCLUSIONS: Our findings demonstrated the feasibility of IHC surrogates to stratify TNBC subtypes with distinct features and prognoses. The IM subtype can be refined by its CD8 spatial pattern. Breast-specific marker expression varied among the subtypes. Marker selection should be tailored accordingly.
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Biomarcadores de Tumor , Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/diagnóstico , Neoplasias de la Mama Triple Negativas/clasificación , Femenino , Persona de Mediana Edad , Pronóstico , Biomarcadores de Tumor/metabolismo , Adulto , Inmunohistoquímica , AncianoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: The anti-tumor related diseases of Coptidis Rhizoma (Huanglian) were correlated with its traditional use of removing damp-heat, clearing internal fire, and counteracting toxicity. In the recent years, Coptidis Rhizoma and its components have drawn extensive attention toward their anti-tumor related diseases. Besides, Coptidis Rhizoma is traditionally used as an anti-inflammatory herb. Epiberberine (EPI) is a significant alkaloid isolated from Coptidis Rhizoma, and exhibits multiple pharmacological activities including anti-inflammatory. However, the effect of epiberberine on breast cancer and the inflammatory factors of metastatic breast cancer-induced osteolysis has not been demonstrated clearly. AIM OF THE STUDY: Bone metastatic breast cancer can lead to osteolysis via inflammatory factors-induced osteoclast differentiation and function. In this study, we try to analyze the effect of epiberberine on breast cancer and the inflammatory factors of metastatic breast cancer-induced osteolysis. METHODS: To evaluate whether epiberberine could suppress bone metastatic breast cancer-induced osteolytic damage, healthy female Balb/c mice were intratibially injected with murine triple-negative breast cancer 4T1 cells. Then, we examined the inhibitory effect and underlying mechanism of epiberberine on breast cancer-induced osteoclastogenesis in vitro. Xenograft assay was used to study the effect of epiberberine on breast cancer cells in vivo. Moreover, we also studied the inhibitory effects and underlying mechanisms of epiberberine on RANKL-induced osteoclast differentiation and function in vitro. RESULTS: The results show that epiberberine displayed potential therapeutic effects on breast cancer-induced osteolytic damage. Besides, our results show that epiberberine inhibited breast cancer cells-induced osteoclast differentiation and function by inhibiting secreted inflammatory cytokines such as IL-8. Importantly, we found that epiberberine directly inhibited RANKL-induced differentiation and function of osteoclast without cytotoxicity. Mechanistically, epiberberine inhibited RANKL-induced osteoclastogensis via Akt/c-Fos signaling pathway. Furthermore, epiberberine combined with docetaxel effectively protected against bone loss induced by metastatic breast cancer cells. CONCLUSIONS: Our findings suggested that epiberberine may be a promising natural compound for treating bone metastatic breast cancer-induced osteolytic damage by inhibiting IL-8 and is worthy of further exploration in preclinical and clinical trials.
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Berberina/análogos & derivados , Neoplasias Óseas , Neoplasias de la Mama , Medicamentos Herbarios Chinos , Osteólisis , Humanos , Femenino , Animales , Ratones , Osteólisis/tratamiento farmacológico , Osteólisis/metabolismo , Osteólisis/patología , Neoplasias de la Mama/patología , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Medicamentos Herbarios Chinos/metabolismo , Interleucina-8/metabolismo , Osteoclastos , Osteogénesis , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Antiinflamatorios/farmacología , Ligando RANK/metabolismoRESUMEN
INTRODUCTION: The recent ACOSOG Z11102 trial demonstrated low recurrence rates with breast conserving surgery (BCS) in women with multiple ipsilateral breast cancers (MIBC). Questions remain regarding the oncologic safety of BCS in women with MIBC receiving neoadjuvant chemotherapy (NAC). METHODS: We conducted a retrospective cohort study of adult patients who underwent BCS following NAC for stage I-III breast cancer from 2012 to 2021 at two academic centers. Descriptive statistics were used to summarize the data and the Kaplan-Meier method was used to provide estimates for recurrence and survival outcomes. MIBC was defined as ≥2 foci of malignancy. RESULTS: A total of 544 patients were included; 29.4% (n = 160) ER+/HER2-, 17.7% (n = 96) ER+/HER2+, 18.2% (n = 99) ER-/HER2+, and 34.7% (n = 189) with ER-/HER2-disease. Overall, 80.5% (n = 438) had unifocal breast cancer while 19.5% (n = 106) had MIBC. Of patients with MIBC, 90.6% (n = 96) had multifocal and 9.4% (n = 10) had multicentric disease. Pathologic complete response was achieved in 41.1% of patients with MIBC versus 41.5% of patients with unifocal disease (p = 0.94). At a median follow-up of 55 months (IQR 32-83); 4.8% of patients in the unifocal group and 4.7% of patients in the MIBC group had had a local recurrence (p = 0.97). There was no difference in 5-year local recurrence-free survival (p = 0.92), recurrence-free survival (p = 0.06), or overall survival (p = 0.07) between the groups. CONCLUSION: In this large cohort of women undergoing BCS post-NAC, there was no significant difference in in breast tumor recurrence or survival outcomes between patients with unifocal disease and those with MIBC.
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Neoplasias de la Mama , Mastectomía Segmentaria , Terapia Neoadyuvante , Humanos , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/cirugía , Neoplasias de la Mama/terapia , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Adulto , Recurrencia Local de Neoplasia , Receptor ErbB-2/metabolismo , Quimioterapia Adyuvante , Receptores de Estrógenos/metabolismo , Estadificación de Neoplasias , Tasa de SupervivenciaRESUMEN
The heterogeneity of triple-negative breast cancers (TNBC) remains challenging for various treatments. Ferroptosis, a recently identified form of cell death resulting from the unrestrained peroxidation of phospholipids, represents a potential vulnerability in TNBC. In this study, a high intensity focused ultrasound (HIFU)-driven nanomotor is developed for effective therapy of TNBC through induction of ferroptosis. Through bioinformatics analysis of typical ferroptosis-associated genes in the FUSCCTNBC dataset, gambogic acid is identified as a promising ferroptosis drug and loaded it into the nanomotor. It is found that the rapid motion of nanomotors propelled by HIFU significantly enhanced tumor accumulation and penetration. More importantly, HIFU not only actuated nanomotors to trigger effective ferroptosis of TNBC cells, but also drove nanomotors to activate ferroptosis-mediated antitumor immunity in primary and metastatic TNBC models, resulting in effective tumor regression and prevention of metastases. Overall, HIFU-driven nanomotors show great potential for ferroptosis-immunotherapy of TNBC.
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Ferroptosis , Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/terapia , Inmunoterapia , Muerte Celular , Biología ComputacionalRESUMEN
BACKGROUND: Immunotherapy has revolutionized the approach to metastatic triple-negative breast cancers. Atezolizumab was approved for patients with metastatic triple-negative breast cancers whose tumors express PD-L1, determined by SP 142 assay. To assess the availability and practice of SP142 test we administered a survey to all the 15 pathology departments of the Lazio Region during a six-month period. METHODS: The survey comprised 12 questions regarding the availability of SP142 in the pathology departments, the percentage of positive tests, the difficulties of pathologists in cases close to cut-off value and the tested samples. RESULTS: The SP142 assay was available in only eight centers. In case of positive result, most centers (5/8, 62.5%) reported values of PD-L1 expression ranging from > 1 to ⩽ 5%, with values close to the cut-off point (⩾ 1% or < 1%) being the greatest challenge.Most of the centers (6/8, 75%) tested material from both their own and other hospitals. In most centers, the evaluations were performed either on primary tumors or metastasis, in particular lymph nodes (5/8, 62.5%), followed by lung (3/8, 37.5%) and liver (1/8, 12.5%) metastasis. CONCLUSION: Our results raise some important issues concerning the evaluation of PD-L1 in the "real-life" setting, providing strategies for its implementation.
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Neoplasias Pulmonares , Neoplasias de la Mama Triple Negativas , Humanos , Inmunohistoquímica , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Antígeno B7-H1/metabolismo , Neoplasias Pulmonares/patología , ItaliaRESUMEN
Triple negative breast cancers (TNBC) are clinically heterogeneous but mostly aggressive malignancies devoid of expression of the estrogen, progesterone, and HER2 (ERBB2 or NEU) receptors. It accounts for 15-20% of all cases. Altered epigenetic regulation including DNA hypermethylation by DNA methyltransferase 1 (DNMT1) has been implicated as one of the causes of TNBC tumorigenesis. The antitumor effect of DNMT1 has also been explored in TNBC that currently lacks targeted therapies. However, the actual treatment for TNBC is yet to be discovered. This study is attributed to the identification of novel drug targets against TNBC. A comprehensive docking and simulation analysis was performed to optimize promising new compounds by estimating their binding affinity to the target protein. Molecular dynamics simulation of 500 ns well complemented the binding affinity of the compound and revealed strong stability of predicted compounds at the docked site. Calculation of binding free energies using MMPBSA and MMGBSA validated the strong binding affinity between compound and binding pockets of DNMT1. In a nutshell, our study uncovered that Beta-Mangostin, Gancaonin Z, 5-hydroxysophoranone, Sophoraflavanone L, and Dorsmanin H showed maximum binding affinity with the active sites of DNMT1. Furthermore, all of these compounds depict maximum drug-like properties. Therefore, the proposed compounds can be a potential candidate for patients with TNBC, but, experimental validation is needed to ensure their safety.Communicated by Ramaswamy H. Sarma.