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1.
Molecules ; 29(11)2024 May 25.
Article in English | MEDLINE | ID: mdl-38893380

ABSTRACT

Breast cancer is a major health concern and the leading cause of death among women worldwide. Standard treatment often involves surgery, radiotherapy, and chemotherapy, but these come with side effects and limitations. Researchers are exploring natural compounds like baicalin and baicalein, derived from the Scutellaria baicalensis plant, as potential complementary therapies. This study investigated the effects of baicalin and baicalein on the cytotoxic, proapoptotic, and genotoxic activity of doxorubicin and docetaxel, commonly used chemotherapeutic drugs for breast cancer. The analysis included breast cancer cells (MCF-7) and human endothelial cells (HUVEC-ST), to assess potential effects on healthy tissues. We have found that baicalin and baicalein demonstrated cytotoxicity towards both cell lines, with more potent effects observed in baicalein. Both flavonoids, baicalin (167 µmol/L) and baicalein (95 µmol/L), synergistically enhanced the cytotoxic, proapoptotic, and genotoxic activity of doxorubicin and docetaxel in breast cancer cells. In comparison, their effects on endothelial cells were mixed and depended on concentration and time. The results suggest that baicalin and baicalein might be promising complementary agents to improve the efficacy of doxorubicin and docetaxel anticancer activity. However, further research is needed to validate their safety and efficacy in clinical trials.


Subject(s)
Apoptosis , Breast Neoplasms , Docetaxel , Doxorubicin , Flavanones , Flavonoids , Humans , Flavonoids/pharmacology , Flavanones/pharmacology , Docetaxel/pharmacology , Doxorubicin/pharmacology , MCF-7 Cells , Apoptosis/drug effects , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Female , DNA Damage/drug effects , Drug Synergism , Antineoplastic Agents/pharmacology , Cell Survival/drug effects , Human Umbilical Vein Endothelial Cells/drug effects
2.
Molecules ; 29(11)2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38893482

ABSTRACT

Apigenin, a naturally derived flavonoid, is increasingly being acknowledged for its potential therapeutic applications, especially in oncology. This research explores apigenin's capacity to modulate cancer cell viability, emphasizing its roles beyond its minimal antioxidant activity attributed to its basic molecular structure devoid of hydroxyl groups. We investigated apigenin's effects on two breast cancer cell lines, estrogen-dependent MCF-7 and non-estrogen-dependent MDA-MB-231 cells. Our findings reveal that apigenin exerts a dose-dependent cytotoxic and anti-migratory impact on these cells. Interestingly, both apigenin and doxorubicin-a standard chemotherapeutic agent-induced lipid droplet accumulation in a dose-dependent manner in MDA-MB-231 cells. This phenomenon was absent in MCF-7 cells and not evident when doxorubicin and apigenin were used concurrently, suggesting distinct cellular responses to these treatments that imply that their synergistic effects might be mediated through mechanisms unrelated to lipid metabolism. A further chemoinformatics analysis indicated that apigenin and doxorubicin might interact primarily at the level of ATP-binding cassette (ABC) transporter proteins, with potential indirect influences from the AKT and MYC signaling pathways. These results highlight the importance of understanding the nuanced interactions between apigenin and conventional chemotherapeutic drugs, as they could lead to more effective strategies for cancer treatment. This study underscores apigenin's potential as a modulator of cancer cell dynamics through mechanisms independent of its direct antioxidant effects, thereby contributing to the development of flavonoid-based adjunct therapies in cancer management.


Subject(s)
Apigenin , Breast Neoplasms , Doxorubicin , Humans , Apigenin/pharmacology , Apigenin/chemistry , Doxorubicin/pharmacology , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Female , Cell Line, Tumor , Cell Survival/drug effects , MCF-7 Cells , Cell Movement/drug effects , Signal Transduction/drug effects , Cell Proliferation/drug effects , Drug Synergism
3.
Cancer Med ; 13(12): e7317, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38895891

ABSTRACT

BACKGROUND: The optimal adjuvant endocrine therapy (ET) in hormone receptor positive (HR+) and human epidermal growth factor receptor 2 positive (HER2+) premenopausal breast cancer (BC) remains unclear. Moreover, the benefit and clinical indications of ovarian suppression (OS) is poorly elucidated. We described real-world patterns surrounding choice of ET and clinicopathologic features which predicted treatment with OS in a contemporary cohort of premenopausal women with HR+/HER2+ BC. METHODS: This retrospective analysis included premenopausal patients with nonmetastatic HR+/HER2+ BC from the CancerLinQ Discovery database from January 2010 to May 2020. Women were less than 50 years and received chemotherapy, anti-HER2 therapy, and ET. They were categorized into 1 of 4 groups based on type of ET prescribed at initiation: aromatase inhibitor (AI) + OS, OS, tamoxifen + OS, or tamoxifen. Multivariable logistic regression assessed associations between clinicopathologic features and OS use. RESULTS: Out of 360,540 patients with BC, 937 were included. The majority (n = 818, 87%) were prescribed tamoxifen, whereas 4 (0.4%), 50 (5.3%), and 65 (6.9%) received OS, tamoxifen + OS and AI + OS, respectively. No clinicopathologic features predicted OS use apart from age; patients <35 years were more likely to receive OS compared with those ≥35 years (odds ratio 2.33, p < 0.001). CONCLUSIONS: This is the first real-world study evaluating ET treatment patterns in HR+/HER2+ premenopausal BC. OS use was uncommon and the majority received tamoxifen as the preferred ET regardless of most clinicopathologic risk factors. Additional research is needed to optimize ET decisions in young women with this distinct BC subtype.


Subject(s)
Antineoplastic Agents, Hormonal , Aromatase Inhibitors , Breast Neoplasms , Premenopause , Receptor, ErbB-2 , Receptors, Estrogen , Tamoxifen , Humans , Female , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Breast Neoplasms/mortality , Adult , Retrospective Studies , Receptor, ErbB-2/metabolism , Chemotherapy, Adjuvant/methods , Antineoplastic Agents, Hormonal/therapeutic use , Tamoxifen/therapeutic use , Aromatase Inhibitors/therapeutic use , Middle Aged , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Ovary/drug effects , Ovary/pathology , Ovary/metabolism
4.
Cancer Med ; 13(12): e7384, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38895905

ABSTRACT

BACKGROUND: Breast cancer is a heterogeneous disease categorized based on molecular characteristics, including hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) expression levels. The emergence of profiling technology has revealed multiple driver genomic alterations within each breast cancer subtype, serving as biomarkers to predict treatment outcomes. This study aimed to explore the genomic landscape of breast cancer in the Taiwanese population through comprehensive genomic profiling (CGP) and identify diagnostic and predictive biomarkers. METHODS: Targeted next-generation sequencing-based CGP was performed on 116 archived Taiwanese breast cancer specimens, assessing genomic alterations (GAs), including single nucleotide variants, copy number variants, fusion genes, tumor mutation burden (TMB), and microsatellite instability (MSI) status. Predictive variants for FDA-approved therapies were evaluated within each subtype. RESULTS: In the cohort, frequent mutations included PIK3CA (39.7%), TP53 (36.2%), KMT2C (9.5%), GATA3 (8.6%), and SF3B1 (6.9%). All subtypes had low TMB, with no MSI-H tumors. Among HR + HER2- patients, 42% (27/65) harbored activating PIK3CA mutations, implying potential sensitivity to PI3K inhibitors and resistance to endocrine therapies. HR + HER2- patients exhibited intrinsic hormonal resistance via FGFR1 gene gain/amplification (15%), exclusive of PI3K/AKT pathway alterations. Aberrations in the PI3K/AKT/mTOR and FGFR pathways were implicated in chemoresistance, with a 52.9% involvement in triple-negative breast cancer. In HER2+ tumors, 50% harbored GAs potentially conferring resistance to anti-HER2 therapies, including PIK3CA mutations (32%), MAP3K1 (2.9%), NF1 (2.9%), and copy number gain/amplification of FGFR1 (18%), FGFR3 (2.9%), EGFR (2.9%), and AKT2 (2.9%). CONCLUSION: This study presents CGP findings for treatment-naïve Taiwanese breast cancer, emphasizing its value in routine breast cancer management, disease classification, and treatment selection.


Subject(s)
Biomarkers, Tumor , Breast Neoplasms , Mutation , Humans , Female , Taiwan , Breast Neoplasms/genetics , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Middle Aged , Biomarkers, Tumor/genetics , Adult , Aged , High-Throughput Nucleotide Sequencing , DNA Copy Number Variations , Genomics/methods , Class I Phosphatidylinositol 3-Kinases/genetics , Microsatellite Instability , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Gene Expression Profiling
5.
Cancer Rep (Hoboken) ; 7(6): e2114, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38886335

ABSTRACT

BACKGROUND: It has been reported that long non-coding RNAs (lncRNAs) can play important roles in a variety of biological processes and cancer regulatory networks, including breast cancer. AIMS: This study aimed to identify a novel upregulated lncRNA in breast cancer and its associated gene using bioinformatics analysis, and then evaluate their potential roles in breast cancer. METHODS AND RESULTS: Extensive in silico studies were performed using various bioinformatics databases and tools to identify a potential upregulated breast cancer-associated lncRNA and its co-expressed gene, and to predict their potential roles, functions, and interactions. The expression level of MRPS30-DT lncRNA and MRPS30 was assessed in both BC tissues and cell lines using qRT-PCR technology. MRPS30-DT lncRNA and MRPS30 were selected as target genes using bioinformatics analysis. We found that MRPS30-DT and MRPS30 were significantly overexpressed in BC tissues compared with normal tissues. Also, MRPS30 showed upregulation in all three BC cell lines compared with HDF. On the other hand, MRPS30-DT significantly increased in MDA-MB-231 compared with HDF. While the expression of MRPS30-DT was significantly dropped in the resistance cell line MCF/MX compared to HDF and MCF7. Moreover, bioinformatics analysis suggested that MRPS30-DT and MRPS30 may play a potential role in BC through their involvement in some cancer signaling pathways and processes, as well as through their interaction with TFs, genes, miRNAs, and proteins related to carcinogenesis. CONCLUSIONS: Overall, our findings showed the dysregulation of MRPS30-DT lncRNA and MRPS30 may provide clues for exploring new therapeutic targets or molecular biomarkers in BC.


Subject(s)
Breast Neoplasms , Computational Biology , Computer Simulation , Gene Expression Regulation, Neoplastic , RNA, Long Noncoding , Humans , RNA, Long Noncoding/genetics , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Female , Computational Biology/methods , Cell Line, Tumor , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Up-Regulation , Cell Proliferation/genetics , MCF-7 Cells , Gene Regulatory Networks
6.
Nat Commun ; 15(1): 5158, 2024 Jun 17.
Article in English | MEDLINE | ID: mdl-38886347

ABSTRACT

Currently approved HER2-targeting antibody-drug conjugates (ADCs) for HER2-positive breast cancer (BC) are associated with safety concerns. In this multicenter, single-arm, dose-escalation (phase 1a) and dose-expansion (phase 1b) phase 1 trial (NCT03944499), patients with HER2-expressing advanced solid tumors received FS-1502 (an anti-HER2 ADC) with a 3 + 3 design in phase 1a; patients with metastatic HER2-positive BC received FS-1502 at the recommended phase 2 dose (RP2D) in phase 1b. The primary end points were dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and RP2D for phase 1a and objective response rate (ORR) for phase 1b. A total of 150 patients with HER2-expressing solid tumors (n = 5) and BC (n = 145) were enrolled (female, n = 146, 97.3%). One DLT each was reported at 3.0 and 3.5 mg/kg; the MTD was not reached. The RP2D was 2.3 mg/kg once every 3 weeks. Five (3.3%) patients experienced pneumonitis; four (2.7%) had grade 3 reversible ocular events. Of 67 HER2-positive BC patients receiving the RP2D, the best ORR was 53.7% (95% CI, 41.1-66.0%), including PRs confirmed (confirmed ORR, 37.5%) and pending for confirmation. FS-1502 was well tolerated with limited ocular and pulmonary findings and demonstrated promising antitumor activity in HER2-positive BC patients.


Subject(s)
Breast Neoplasms , Immunoconjugates , Maximum Tolerated Dose , Receptor, ErbB-2 , Humans , Female , Receptor, ErbB-2/metabolism , Receptor, ErbB-2/genetics , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Immunoconjugates/therapeutic use , Immunoconjugates/administration & dosage , Middle Aged , Aged , Adult , Aged, 80 and over , Neoplasm Metastasis , Male
7.
Nat Commun ; 15(1): 5154, 2024 Jun 17.
Article in English | MEDLINE | ID: mdl-38886378

ABSTRACT

Cancer incidence escalates exponentially with advancing age; however, the underlying mechanism remains unclear. In this study, we build a chronological molecular clock at single-cell transcription level with a mammary stem cell-enriched population to depict physiological aging dynamics in female mice. We find that the mammary aging process is asynchronous and progressive, initiated by an early senescence program, succeeded by an entropic late senescence program with elevated cancer associated pathways, vulnerable to cancer predisposition. The transition towards senescence program is governed by a stem cell factor Bcl11b, loss of which accelerates mammary ageing with enhanced DMBA-induced tumor formation. We have identified a drug TPCA-1 that can rejuvenate mammary cells and significantly reduce aging-related cancer incidence. Our findings establish a molecular portrait of progressive mammary cell aging and elucidate the transcriptional regulatory network bridging mammary aging and cancer predisposition, which has potential implications for the management of cancer prevalence in the aged.


Subject(s)
Aging , Breast Neoplasms , Cellular Senescence , Female , Animals , Mice , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Breast Neoplasms/genetics , Humans , Mammary Glands, Animal/pathology , Mammary Glands, Animal/metabolism , Stem Cells/metabolism
8.
Nat Commun ; 15(1): 5152, 2024 Jun 17.
Article in English | MEDLINE | ID: mdl-38886396

ABSTRACT

In many cancers, a stem-like cell subpopulation mediates tumor initiation, dissemination and drug resistance. Here, we report that cancer stem cell (CSC) abundance is transcriptionally regulated by C-terminally phosphorylated p27 (p27pT157pT198). Mechanistically, this arises through p27 co-recruitment with STAT3/CBP to gene regulators of CSC self-renewal including MYC, the Notch ligand JAG1, and ANGPTL4. p27pTpT/STAT3 also recruits a SIN3A/HDAC1 complex to co-repress the Pyk2 inhibitor, PTPN12. Pyk2, in turn, activates STAT3, creating a feed-forward loop increasing stem-like properties in vitro and tumor-initiating stem cells in vivo. The p27-activated gene profile is over-represented in STAT3 activated human breast cancers. Furthermore, mammary transgenic expression of phosphomimetic, cyclin-CDK-binding defective p27 (p27CK-DD) increases mammary duct branching morphogenesis, yielding hyperplasia and microinvasive cancers that can metastasize to liver, further supporting a role for p27pTpT in CSC expansion. Thus, p27pTpT interacts with STAT3, driving transcriptional programs governing stem cell expansion or maintenance in normal and cancer tissues.


Subject(s)
Breast Neoplasms , Cyclin-Dependent Kinase Inhibitor p27 , Hyperplasia , Neoplastic Stem Cells , STAT3 Transcription Factor , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Humans , Cyclin-Dependent Kinase Inhibitor p27/metabolism , Cyclin-Dependent Kinase Inhibitor p27/genetics , Animals , STAT3 Transcription Factor/metabolism , STAT3 Transcription Factor/genetics , Female , Phosphorylation , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Hyperplasia/metabolism , Mice , Gene Expression Regulation, Neoplastic , Cell Self Renewal/genetics , Cell Line, Tumor , Mammary Glands, Animal/metabolism , Mammary Glands, Animal/pathology , Mammary Glands, Animal/cytology , Jagged-1 Protein/metabolism , Jagged-1 Protein/genetics
9.
Sci Rep ; 14(1): 13935, 2024 06 17.
Article in English | MEDLINE | ID: mdl-38886516

ABSTRACT

Breast cancer is one of the tumors with the highest prevalence rate among women in the world, and its BRCA1/2 gene is a common mutation site. Talazoparib, as a targeted PARP inhibitor, can effectively control the occurrence and development of breast cancer with BRCA1/2 gene mutation, and play a therapeutic role. Based on the findings from the Phase III EMBRACE trial (NCT01945775 clinical trial), our analysis reveals that the talazoparib group demonstrated a significant extension in progression-free survival, along with improved response markers and patient-reported outcomes when compared to conventional therapies. This study aims to assess the cost-effectiveness of talazoparib for treating advanced breast cancer with germline BRCA1/2 mutations and HER2 negativity, considering the perspectives of health services in China and the United States. The results obtained will serve as a valuable reference for promoting rational drug utilization and enhancing medical resource efficiency. To evaluate the cost-effectiveness of Talazoparib more scientifically and provide clinicians with chemotherapy options, this paper developed a Markov model based on the EMBRACA clinical trial (clinical Trails.gov No., NCT01945775) to simulate the survival events of breast cancer patients in the Talazoparib group and the standard treatment group. The state transition probability and clinical data of breast cancer patients during treatment were extracted from the phase III EMBRACA clinical trial. The cost data generated during the treatment process comes from local hospital pricing, other references, and expert consultation. This article uses US dollars to calculate the treatment cost and incremental cost-effectiveness ratio. Health outcomes are expressed in Quality Adjusted Life Years (QALYs). In addition, Outcomes were measured in quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio, which robustness was evaluated by deterministic and probabilistic sensitivity analyses. This article establishes a Markov model for single-item sensitivity analysis. The results show that the economic benefits of using Talazoparib as a new treatment strategy in both China and the United States are higher than other drugs, and it is cost-effective. Compared to the control group, the incremental cost incurred by the Talazoparib treatment group in China was $2484.48/QALY, with an incremental QALY of 1.5. However, Talazoparib in the United States holds a dominant position, saving costs of $10,223.43 and increasing QALYs by 1.5. The clinical treatment effect of Talazoparib group in BRCA1/2 mutant advanced breast cancer patients is better than that of the standard treatment group, and the progression free survival period is significantly prolonged. From the perspective of medical and health services in China and the United States, the Talazoparib group is more economical than the standard treatment group in treating patients with BRCA1/2 mutant advanced breast cancer.


Subject(s)
BRCA1 Protein , BRCA2 Protein , Breast Neoplasms , Cost-Benefit Analysis , Germ-Line Mutation , Phthalazines , Receptor, ErbB-2 , Humans , Female , Phthalazines/therapeutic use , Phthalazines/economics , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/economics , Breast Neoplasms/pathology , China , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , BRCA2 Protein/genetics , United States , BRCA1 Protein/genetics , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Poly(ADP-ribose) Polymerase Inhibitors/economics , Quality-Adjusted Life Years , Middle Aged , Markov Chains , Adult , Progression-Free Survival
10.
J Exp Clin Cancer Res ; 43(1): 171, 2024 Jun 18.
Article in English | MEDLINE | ID: mdl-38886784

ABSTRACT

BACKGROUND: The cyclin D1-cyclin dependent kinases (CDK)4/6 inhibitor palbociclib in combination with endocrine therapy shows remarkable efficacy in the management of estrogen receptor (ER)-positive and HER2-negative advanced breast cancer (BC). Nevertheless, resistance to palbociclib frequently arises, highlighting the need to identify new targets toward more comprehensive therapeutic strategies in BC patients. METHODS: BC cell lines resistant to palbociclib were generated and used as a model system. Gene silencing techniques and overexpression experiments, real-time PCR, immunoblotting and chromatin immunoprecipitation studies as well as cell viability, colony and 3D spheroid formation assays served to evaluate the involvement of the G protein-coupled estrogen receptor (GPER) in the resistance to palbociclib in BC cells. Molecular docking simulations were also performed to investigate the potential interaction of palbociclib with GPER. Furthermore, BC cells co-cultured with cancer-associated fibroblasts (CAFs) isolated from mammary carcinoma, were used to investigate whether GPER signaling may contribute to functional cell interactions within the tumor microenvironment toward palbociclib resistance. Finally, by bioinformatics analyses and k-means clustering on clinical and expression data of large cohorts of BC patients, the clinical significance of novel mediators of palbociclib resistance was explored. RESULTS: Dissecting the molecular events that characterize ER-positive BC cells resistant to palbociclib, the down-regulation of ERα along with the up-regulation of GPER were found. To evaluate the molecular events involved in the up-regulation of GPER, we determined that the epidermal growth factor receptor (EGFR) interacts with the promoter region of GPER and stimulates its expression toward BC cells resistance to palbociclib treatment. Adding further cues to these data, we ascertained that palbociclib does induce pro-inflammatory transcriptional events via GPER signaling in CAFs. Of note, by performing co-culture assays we demonstrated that GPER contributes to the reduced sensitivity to palbociclib also facilitating the functional interaction between BC cells and main components of the tumor microenvironment named CAFs. CONCLUSIONS: Overall, our results provide novel insights on the molecular events through which GPER may contribute to palbociclib resistance in BC cells. Additional investigations are warranted in order to assess whether targeting the GPER-mediated interactions between BC cells and CAFs may be useful in more comprehensive therapeutic approaches of BC resistant to palbociclib.


Subject(s)
Breast Neoplasms , Cyclin-Dependent Kinase 4 , Drug Resistance, Neoplasm , Piperazines , Pyridines , Receptors, Estrogen , Humans , Pyridines/pharmacology , Pyridines/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Breast Neoplasms/genetics , Piperazines/pharmacology , Piperazines/therapeutic use , Female , Receptors, Estrogen/metabolism , Cyclin-Dependent Kinase 4/metabolism , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cell Line, Tumor , Receptors, G-Protein-Coupled/metabolism , Cyclin-Dependent Kinase 6/metabolism , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Tumor Microenvironment
11.
Breast Cancer Res ; 26(1): 102, 2024 Jun 17.
Article in English | MEDLINE | ID: mdl-38886818

ABSTRACT

BACKGROUND: Early menarche is an established risk factor for breast cancer but its molecular contribution to tumor biology and prognosis remains unclear. METHODS: We profiled transcriptome-wide gene expression in breast tumors (N = 846) and tumor-adjacent normal tissues (N = 666) from women in the Nurses' Health Studies (NHS) to investigate whether early menarche (age < 12) is associated with tumor molecular and prognostic features in women with breast cancer. Multivariable linear regression and pathway analyses using competitive gene set enrichment analysis were conducted in both tumor and adjacent-normal tissue and externally validated in TCGA (N = 116). Subgroup analyses stratified on ER-status based on the tumor were also performed. PAM50 signatures were used for tumor molecular subtyping and to generate proliferation and risk of recurrence scores. We created a gene expression score using LASSO regression to capture early menarche based on 28 genes from FDR-significant pathways in breast tumor tissue in NHS and tested its association with 10-year disease-free survival in both NHS (N = 836) and METABRIC (N = 952). RESULTS: Early menarche was significantly associated with 369 individual genes in adjacent-normal tissues implicated in extracellular matrix, cell adhesion, and invasion (FDR ≤ 0.1). Early menarche was associated with upregulation of cancer hallmark pathways (18 significant pathways in tumor, 23 in tumor-adjacent normal, FDR ≤ 0.1) related to proliferation (e.g. Myc, PI3K/AKT/mTOR, cell cycle), oxidative stress (e.g. oxidative phosphorylation, unfolded protein response), and inflammation (e.g. pro-inflammatory cytokines IFN α and IFN γ ). Replication in TCGA confirmed these trends. Early menarche was associated with significantly higher PAM50 proliferation scores (ß = 0.082 [0.02-0.14]), odds of aggressive molecular tumor subtypes (basal-like, OR = 1.84 [1.18-2.85] and HER2-enriched, OR = 2.32 [1.46-3.69]), and PAM50 risk of recurrence score (ß = 4.81 [1.71-7.92]). Our NHS-derived early menarche gene expression signature was significantly associated with worse 10-year disease-free survival in METABRIC (N = 952, HR = 1.58 [1.10-2.25]). CONCLUSIONS: Early menarche is associated with more aggressive molecular tumor characteristics and its gene expression signature within tumors is associated with worse 10-year disease-free survival among women with breast cancer. As the age of onset of menarche continues to decline, understanding its relationship to breast tumor characteristics and prognosis may lead to novel secondary prevention strategies.


Subject(s)
Breast Neoplasms , Gene Expression Profiling , Menarche , Neoplasm Recurrence, Local , Transcriptome , Humans , Female , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Breast Neoplasms/mortality , Menarche/genetics , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Middle Aged , Prognosis , Adult , Biomarkers, Tumor/genetics , Risk Factors , Gene Expression Regulation, Neoplastic , Age Factors
12.
J Int Med Res ; 52(6): 3000605241259682, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38886869

ABSTRACT

OBJECTIVE: To compare the staining quality between rapid hematoxylin and eosin (H&E) staining and routine H&E staining of frozen breast tissue sections. METHODS: In this cross-sectional observational study, 120 frozen breast tissue sections were randomly assigned to rapid or routine H&E staining (n = 60 per group). Rapid H&E staining used a 7:1 mixture of modified Gill's hematoxylin and alcohol-soluble 1% eosin Y. The staining quality of each section was evaluated and scored. A score of >7 was considered excellent, a score of 6 to 7 good, and a score of ≤5 poor. RESULTS: The staining time for rapid staining was approximately 3 minutes, whereas that of routine staining was approximately 12 minutes. There were no significant differences in the staining quality scores or proportions of sections in each grade between the two staining methods. The proportions of sections that were classified as excellent or good were 96.7% and 98.3% for rapid and routine staining, respectively. CONCLUSIONS: In frozen breast tissue sections, rapid H&E staining may provide staining quality that is comparable to that of routine staining, while markedly reducing the staining time.


Subject(s)
Breast , Eosine Yellowish-(YS) , Frozen Sections , Hematoxylin , Staining and Labeling , Humans , Female , Staining and Labeling/methods , Frozen Sections/methods , Breast/pathology , Cross-Sectional Studies , Middle Aged , Adult , Breast Neoplasms/pathology , Aged
13.
JMIR Res Protoc ; 13: e52361, 2024 Jun 18.
Article in English | MEDLINE | ID: mdl-38889402

ABSTRACT

BACKGROUND: Receiving a diagnosis of cancer is a profound and often very stressful experience. Few studies have prospectively recruited patients prior to receiving a new diagnosis of cancer and included spouses or partners. OBJECTIVE: The aim of the Couples Cope Study is to understand the impact of undergoing a diagnostic biopsy and receiving a new cancer diagnosis on quality of life (QoL) in both patients and their spouses or partners, as well as on the quality of their relationship. This protocol paper describes the study design and assesses the feasibility of recruitment and retention. METHODS: Study staff reviewed the schedules of collaborating physicians using specific encounter codes to identify patients scheduled for breast or prostate biopsies. Potential participants were prescreened via the electronic health record and sent a recruitment letter at least 2 to 3 weeks prior to their biopsy procedure. Patients subsequently underwent a phone screening to determine eligibility. Patients who enrolled provided study staff with contact information for their spouses or partners. All consent forms were completed online. Surveys were completed online prior to receiving the biopsy results (baseline), and at 1, 3, 6, and 9 months after the biopsy. Study staff engaged in ongoing, personalized contact with participants and sent assessment completion reminders via phone and email. RESULTS: A total of 2294 patients undergoing a breast or prostate biopsy were identified and 69% (n=1582) were eligible for phone screening following electronic health record prescreening. Of the 431 patients who underwent phone screening, 75% (n=321) were eligible to participate. Of the eligible patients, 72% (n=231) enrolled and 82% (n=190) of enrolled patients had an accompanying partner or spouse who also enrolled. A total of 77% (34/44) of patients who received a cancer diagnosis and 72% (26/36) of their spouses or partners were retained through 9 months, while 80% (53/66) of patients who received a benign diagnosis and 68% (42/62) of their partners were retained. CONCLUSIONS: Prospective recruitment of patients undergoing diagnostic biopsy and their partners is feasible and requires both strategic collaboration with providers and concerted prescreening and recruitment efforts by study staff. Importantly, this study was able to conduct all study activities online without disrupting clinical workflow and without requiring patients and their spouses or partners to come into the laboratory. Consideration should be given to the ratio of biopsies to cancer diagnoses, which can vary significantly by cancer type. Prospective studies are needed and can inform our ability to provide effective support earlier to couples facing a possible cancer diagnosis. Future studies should examine other tumor types that have received less attention in QoL studies, include behavioral and neurobiological assessments beyond self-report measures, and follow couples beyond 9 months in order to examine long-term effects on QoL. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/52361.


Subject(s)
Quality of Life , Spouses , Humans , Spouses/psychology , Prospective Studies , Male , Quality of Life/psychology , Female , Biopsy/psychology , Biopsy/methods , Breast Neoplasms/pathology , Breast Neoplasms/psychology , Breast Neoplasms/diagnosis , Prostatic Neoplasms/pathology , Prostatic Neoplasms/psychology , Prostatic Neoplasms/diagnosis , Middle Aged , Adult , Neoplasms/psychology , Neoplasms/pathology , Neoplasms/diagnosis , Aged
14.
Hum Genomics ; 18(1): 68, 2024 Jun 18.
Article in English | MEDLINE | ID: mdl-38890714

ABSTRACT

BACKGROUND: In Colombia and worldwide, breast cancer (BC) is the most frequently diagnosed neoplasia and the leading cause of death from cancer among women. Studies predominantly involve hereditary and familial cases, demonstrating a gap in the literature regarding the identification of germline mutations in unselected patients from Latin-America. Identification of pathogenic/likely pathogenic (P/LP) variants is important for shaping national genetic analysis policies, genetic counseling, and early detection strategies. The present study included 400 women with unselected breast cancer (BC), in whom we analyzed ten genes, using Whole Exome Sequencing (WES), know to confer risk for BC, with the aim of determining the genomic profile of previously unreported P/LP variants in the affected population. Additionally, Multiplex Ligation-dependent Probe Amplification (MLPA) was performed to identify Large Genomic Rearrangements (LGRs) in the BRCA1/2 genes. To ascertain the functional impact of a recurrent intronic variant (ATM c.5496 + 2_5496 + 5delTAAG), a minigene assay was conducted. RESULTS: We ascertained the frequency of P/LP germline variants in BRCA2 (2.5%), ATM (1.25%), BRCA1 (0.75%), PALB2 (0.50%), CHEK2 (0.50%), BARD1 (0.25%), and RAD51D (0.25%) genes in the population of study. P/LP variants account for 6% of the total population analyzed. No LGRs were detected in our study. We identified 1.75% of recurrent variants in BRCA2 and ATM genes. One of them corresponds to the ATM c.5496 + 2_5496 + 5delTAAG. Functional validation of this variant demonstrated a splicing alteration probably modifying the Pincer domain and subsequent protein structure. CONCLUSION: This study described for the first time the genomic profile of ten risk genes in Colombian women with unselected BC. Our findings underscore the significance of population-based research, advocating the consideration of molecular testing in all women with cancer.


Subject(s)
BRCA2 Protein , Breast Neoplasms , Genetic Predisposition to Disease , Germ-Line Mutation , Humans , Female , Germ-Line Mutation/genetics , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Breast Neoplasms/epidemiology , Colombia/epidemiology , Middle Aged , Adult , BRCA2 Protein/genetics , BRCA1 Protein/genetics , Exome Sequencing , Aged , Genetic Testing/methods , Ataxia Telangiectasia Mutated Proteins/genetics
15.
Cells ; 13(11)2024 May 24.
Article in English | MEDLINE | ID: mdl-38891038

ABSTRACT

Eukaryotic cells tether the nucleoskeleton to the cytoskeleton via a conserved molecular bridge, called the LINC complex. The core of the LINC complex comprises SUN-domain and KASH-domain proteins that directly associate within the nuclear envelope lumen. Intra- and inter-chain disulphide bonds, along with KASH-domain protein interactions, both contribute to the tertiary and quaternary structure of vertebrate SUN-domain proteins. The significance of these bonds and the role of PDIs (protein disulphide isomerases) in LINC complex biology remains unclear. Reducing and non-reducing SDS-PAGE analyses revealed a prevalence of SUN2 homodimers in non-tumorigenic breast epithelia MCF10A cells, but not in the invasive triple-negative breast cancer MDA-MB-231 cell line. Furthermore, super-resolution microscopy revealed SUN2 staining alterations in MCF10A, but not in MDA-MB-231 nuclei, upon reducing agent exposure. While PDIA1 levels were similar in both cell lines, pharmacological inhibition of PDI activity in MDA-MB-231 cells led to SUN-domain protein down-regulation, as well as Nesprin-2 displacement from the nucleus. This inhibition also caused changes in perinuclear cytoskeletal architecture and lamin downregulation, and increased the invasiveness of PDI-inhibited MDA-MB-231 cells in space-restrictive in vitro environments, compared to untreated cells. These results emphasise the key roles of PDIs in regulating LINC complex biology, cellular architecture, biomechanics, and invasion.


Subject(s)
Neoplasm Invasiveness , Protein Disulfide-Isomerases , Humans , Cell Line, Tumor , Protein Disulfide-Isomerases/metabolism , Female , Down-Regulation/drug effects , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Membrane Proteins/metabolism , Nuclear Proteins/metabolism , Nuclear Envelope/metabolism , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/pathology , Intracellular Signaling Peptides and Proteins
16.
Sci Rep ; 14(1): 13497, 2024 06 12.
Article in English | MEDLINE | ID: mdl-38866982

ABSTRACT

Antimicrobial peptides (AMPs) have sparked significant interest as potential anti-cancer agents, thereby becoming a focal point in pursuing novel cancer-fighting strategies. These peptides possess distinctive properties, underscoring the importance of developing more potent and selectively targeted versions with diverse mechanisms of action against human cancer cells. Such advancements would offer notable advantages compared to existing cancer therapies. This research aimed to examine the toxicity and selectivity of the nrCap18 peptide in both cancer and normal cell lines. Furthermore, the rate of cellular death was assessed using apoptosis and acridine orange/ethidium bromide (AO/EB) double staining at three distinct incubation times. Additionally, the impact of this peptide on the cancer cell cycle and migration was evaluated, and ultimately, the expression of cyclin-dependent kinase 4/6 (CDK4/6) genes was investigated. The results obtained from the study demonstrated significant toxicity and selectivity in cancer cells compared to normal cells. Moreover, a strong progressive increase in cell death was observed over time. Furthermore, the peptide exhibited the ability to halt the progression of cancer cells in the G1 phase of the cell cycle and impede their migration by suppressing the expression of CDK4/6 genes.


Subject(s)
Apoptosis , Breast Neoplasms , Cathelicidins , Cyclin-Dependent Kinase 4 , Humans , Animals , Cell Line, Tumor , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Apoptosis/drug effects , Cyclin-Dependent Kinase 4/metabolism , Cyclin-Dependent Kinase 4/genetics , Female , Rabbits , Cell Movement/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antimicrobial Cationic Peptides/pharmacology , Cyclin-Dependent Kinase 6/metabolism , Cell Cycle/drug effects , Cell Proliferation/drug effects , Peptides/pharmacology , Peptides/chemistry , Gene Expression Regulation, Neoplastic/drug effects
17.
Breast Cancer Res ; 26(1): 99, 2024 Jun 12.
Article in English | MEDLINE | ID: mdl-38867302

ABSTRACT

In this study, we prepared a bionic nanosystem of trastuzumab-functionalized SK-BR-3 cell membrane hybrid liposome-coated pyrotinib (Ptb-M-Lip-Her) for the treatment of HER2-positive breast cancer. Transmission electron microscopy, dynamic light scattering, polyacrylamide gel electrophoresis (SDS-PAGE) and western blotting were used to verify the successful preparation of Ptb-M-Lip-Her. In vitro drug release experiments proved that Ptb-M-Lip-Her had a sustained release effect. Cell uptake experiments and in vivo imaging experiments proved that Ptb-M-Lip-Her had good targeting ability to homologous tumor cells (SK-BR-3). The results of cell experiments such as MTT, flow cytometry, immunofluorescence staining and in vivo antitumor experiments showed that Ptb-M-Lip-Her could significantly promote apoptosis and inhibit the proliferation of SK-BR-3 cells. These results clearly indicated that Ptb-M-Lip-Her may be a promising biomimetic nanosystem for targeted therapy of HER2-positive breast cancer.


Subject(s)
Apoptosis , Breast Neoplasms , Liposomes , Receptor, ErbB-2 , Trastuzumab , Xenograft Model Antitumor Assays , Humans , Female , Liposomes/chemistry , Trastuzumab/administration & dosage , Trastuzumab/pharmacology , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Receptor, ErbB-2/metabolism , Animals , Cell Line, Tumor , Mice , Apoptosis/drug effects , Cell Proliferation/drug effects , Drug Liberation , Drug Delivery Systems , Molecular Targeted Therapy , Acrylamides , Aminoquinolines
18.
Breast Cancer Res ; 26(1): 100, 2024 Jun 12.
Article in English | MEDLINE | ID: mdl-38867307

ABSTRACT

BACKGROUND: Immunohistochemistry (IHC) and in situ hybridization (ISH) remain standard biomarkers for therapeutic decisions in human epidermal growth factor 2 (HER2)-positive breast cancers (BCs); however, they are insufficient to explain the heterogeneous anti-HER2 response. METHODS: We aimed to investigate the correlation of in situ HER2 RNA expression (isHRE), using RNAscope, with HER2 biomarkers and the impact of isHRE on the pathological complete response (pCR) rates of 278 patients with HER2 IHC/fluorescence ISH (FISH)-positive BC receiving neoadjuvant chemotherapy and anti-HER2 targeted treatment (NCTT). RESULTS: We validated HER2 RNAscope scoring as a semiquantitative method to determine isHRE and showed a positive correlation between RNAscope scores and pCR rates, with particularly different rates between patients with a score of 5 versus 1-4 BCs (66.7% vs. 15.9%, p < 0.0001). There were higher RNAscope scores and pCR rates in patients with HER2 IHC 3 + versus IHC 2+/FISH + BCs and HER2 RNAscope scores and pCR rates showed similar non-linear positive correlations with HER2 copy numbers and HER2/centromere 17 ratios. Moreover, in each HER2-positive IHC/FISH category, higher pCR rates were observed in patients with RNAscope scores of 5 versus 1-4 BC. Patients achieving pCR had BCs with notably higher HER2 RNAscope scores. Multivariate analysis identified HER2 RNAscope 5 as a strong pCR predictor [odds ratio = 10.865, p < 0.001]. The combined impact of multivariate analysis-defined pCR predictors demonstrated that a higher pCR rate was observed in patients with a score of 5 versus a score of 1-4 BCs regardless of the status of hormone receptor and mono-or dual anti-HER2 blockade. CONCUSIONS: Our results demonstrated that high isHRE (RNAscope score 5) is a strong pCR predictor in patients with HER2-positive BCs receiving NCTT, highlighting the complementary role of isHRE in stratifying HER2 status in tissue. Such stratification is relevant to anti-HER2 therapeutic efficacy, particularly using the cutoff of score 1-4 versus 5.


Subject(s)
Biomarkers, Tumor , Breast Neoplasms , In Situ Hybridization, Fluorescence , Neoadjuvant Therapy , Receptor, ErbB-2 , Humans , Receptor, ErbB-2/metabolism , Receptor, ErbB-2/genetics , Female , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Neoadjuvant Therapy/methods , Middle Aged , Adult , Biomarkers, Tumor/metabolism , Aged , Treatment Outcome , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Molecular Targeted Therapy , Immunohistochemistry , Prognosis , Trastuzumab/therapeutic use , Pathologic Complete Response
19.
Breast Cancer Res ; 26(1): 98, 2024 Jun 12.
Article in English | MEDLINE | ID: mdl-38867323

ABSTRACT

BACKGROUND: The differential gene expression profile of metastatic versus primary breast tumors represents an avenue for discovering new or underappreciated pathways underscoring processes of metastasis. However, as tumor biopsy samples are a mixture of cancer and non-cancer cells, most differentially expressed genes in metastases would represent confounders involving sample biopsy site rather than cancer cell biology. METHODS: By paired analysis, we defined a top set of differentially expressed genes in breast cancer metastasis versus primary tumors using an RNA-sequencing dataset of 152 patients from The Breast International Group Aiming to Understand the Molecular Aberrations dataset (BIG-AURORA). To filter the genes higher in metastasis for genes essential for breast cancer proliferation, we incorporated CRISPR-based data from breast cancer cell lines. RESULTS: A significant fraction of genes with higher expression in metastasis versus paired primary were essential by CRISPR. These 264 genes represented an essential signature of breast cancer metastasis. In contrast, nonessential metastasis genes largely involved tumor biopsy site. The essential signature predicted breast cancer patient outcome based on primary tumor expression patterns. Pathways underlying the essential signature included proteasome degradation, the electron transport chain, oxidative phosphorylation, and cancer metabolic reprogramming. Transcription factors MYC, MAX, HDAC3, and HCFC1 each bound significant fractions of essential genes. CONCLUSIONS: Associations involving the essential gene signature of breast cancer metastasis indicate true biological changes intrinsic to cancer cells, with important implications for applying existing therapies or developing alternate therapeutic approaches.


Subject(s)
Breast Neoplasms , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Neoplasm Metastasis , Transcriptome , Humans , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Female , Biomarkers, Tumor/genetics , Genes, Essential/genetics , Cell Line, Tumor , Signal Transduction/genetics , Prognosis
20.
Breast Dis ; 43(1): 187-191, 2024.
Article in English | MEDLINE | ID: mdl-38875024

ABSTRACT

An 85-year-old Chinese lady presented with a 5-day history of a painless left breast lump. There was no fever, nipple discharge, or history of trauma. She had a past medical history of atrial fibrillation that was managed with an oral anticoagulant. Mammography demonstrated a dense mass in the upper outer quadrant of the left breast. Ultrasound showed an irregular, heterogeneous 4.7 cm lesion containing debris and cystic spaces with raised peripheral vascularity at the 2 o'clock position, 3 cm from nipple. No internal vascularity was detected. This was managed as a haematoma and rivaroxaban was withheld. Follow-up imaging 3-weeks later showed persistence of the lesion. Bedside needle aspiration yielded haemoserous fluid with immediate reduction in size of the lesion. However, 2 weeks after aspiration, there was recurrence of the 'haematoma'. Multidisciplinary review of the clinical history, examination and imaging was sought, and biopsy of the irregularly thickened areas with vascularity along the periphery of the lesion was recommended. Vacuum-assisted biopsy was performed, and histology returned as metaplastic carcinoma. A recurring 'haematoma' should always prompt a search for a secondary cause, with features such as irregular thickened walls and papillary/nodular components requiring further evaluation with biopsy for histopathological correlation.


Subject(s)
Breast Neoplasms , Hematoma , Humans , Female , Hematoma/diagnostic imaging , Breast Neoplasms/diagnosis , Breast Neoplasms/pathology , Aged, 80 and over , Diagnosis, Differential , Mammography , Metaplasia , Recurrence
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