scholarly journals Breast cancer growth and proliferation is suppressed by the mitochondrial targeted furazano[3,4-b]pyrazine BAM15

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Elizabeth R. M. Zunica ◽  
Christopher L. Axelrod ◽  
Eunhan Cho ◽  
Guillaume Spielmann ◽  
Gangarao Davuluri ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Oxidative Phosphorylation ◽  
Energy Production ◽  
Coupling Efficiency ◽  
Breast Cancers ◽  
Mitochondrial Uncoupling ◽  
Transcriptomic Profiling ◽  
Atp Production ◽  
Luminal B

Abstract Background Enhanced metabolic plasticity and diversification of energy production is a hallmark of highly proliferative breast cancers. This contributes to poor pharmacotherapy efficacy, recurrence, and metastases. We have previously identified a mitochondrial-targeted furazano[3,4-b]pyrazine named BAM15 that selectively reduces bioenergetic coupling efficiency and is orally available. Here, we evaluated the antineoplastic properties of uncoupling oxidative phosphorylation from ATP production in breast cancer using BAM15. Methods The anticancer effects of BAM15 were evaluated in human triple-negative MDA-MB-231 and murine luminal B, ERα-negative EO771 cells as well as in an orthotopic allograft model of highly proliferative mammary cancer in mice fed a standard or high fat diet (HFD). Untargeted transcriptomic profiling of MDA-MB-231 cells was conducted after 16-h exposure to BAM15. Additionally, oxidative phosphorylation and electron transfer capacity was determined in permeabilized cells and excised tumor homogenates after treatment with BAM15. Results BAM15 increased proton leak and over time, diminished cell proliferation, migration, and ATP production in both MDA-MB-231 and EO771 cells. Additionally, BAM15 decreased mitochondrial membrane potential, while inducing apoptosis and reactive oxygen species accumulation in MDA-MB-231 and EO771 cells. Untargeted transcriptomic profiling of MDA-MB-231 cells further revealed inhibition of signatures associated with cell survival and energy production by BAM15. In lean mice, BAM15 lowered body weight independent of food intake and slowed tumor progression compared to vehicle-treated controls. In HFD mice, BAM15 reduced tumor growth relative to vehicle and calorie-restricted weight-matched controls mediated in part by impaired cell proliferation, mitochondrial respiratory function, and ATP production. LC-MS/MS profiling of plasma and tissues from BAM15-treated animals revealed distribution of BAM15 in adipose, liver, and tumor tissue with low abundance in skeletal muscle. Conclusions Collectively, these data indicate that mitochondrial uncoupling may be an effective strategy to limit proliferation of aggressive forms of breast cancer. More broadly, these findings highlight the metabolic vulnerabilities of highly proliferative breast cancers which may be leveraged in overcoming poor responsiveness to existing therapies.

Molecular profiles of genomically high risk ER+ HER2- breast cancer tumors classified as functionally basal or luminal B by the 80-gene signature.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 563-563
Author(s):  
Joyce O'Shaughnessy ◽  
Virginia G. Kaklamani ◽  
Yuan Yuan ◽  
Julie Barone ◽  
Sami Diab ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
High Risk ◽  
Neoadjuvant Chemotherapy ◽  
Enrichment Analysis ◽  
Gene Signature ◽  
Breast Cancers ◽  
Luminal B ◽  
Estrogen Response ◽  
Luminal Type ◽  
Basal Type

563 Background: The 80-gene signature (BluePrint/BP) classifies early-stage breast cancers based on functional molecular pathways as luminal, HER2, or Basal-type. In the NBRST study, 13% of immunochemistry (IHC) defined ER+ HER2- cancers reclassified as Basal-type by the BP assay (ER+ Basal), and these had worse prognosis but responded better to neoadjuvant chemotherapy than ER+ HER2- cancers classified as genomically luminal-type. The 70-gene risk of recurrence signature (MammaPrint/MP) further stratifies luminal-type cancers into low risk luminal A or high risk (HR) luminal B. HR cancers can be further stratified into High 1 (H1) or High 2 (H2), and the I-SPY2 trial has shown higher pCR rates in ER+ cancers classified as H2. Here, we investigated biological differences among ER+ Basal, ER- Basal, H1 luminal B, and H2 luminal B cancers by full transcriptome analysis. Methods: From the FLEX Study (NCT03053193), 1501 breast cancers with known IHC ER status were classified by MP and BP: 103 ER+ Basal, 210 ER- Basal and 1188 luminal B (H1 n=1034, H2 n=154). Clinical factors were assessed by either the Chi-square or Fisher’s exact tests; ANOVA or t test were used to analyze age. Differentially expressed genes (DEGs) were detected using Limma and pathway analyses were performed with GSEA. DEGs with a fold change >2 and FDR < 0.05 were considered significant. Results: Basal-type cancers (ER+/ER-) were larger and higher grade than luminal B cancers. Clustering analysis showed similar transcriptional profiles between ER+ Basal and ER- Basal cancers, distinct from luminal B cancers. Few DEGs were detected between ER+ Basal and ER- Basal cancers, and significantly more DEGs were found between ER+ Basal and luminal B cancers. Only three upregulated genes were detected in ER+ Basal compared to ER- Basal cancers: ESR1 and two immune-related genes ( FDCSP and LTF). Enrichment analysis of DEGs indicated increased immune activation and cell proliferation in ER+ Basal and ER- Basal cancers, and decreased estrogen response between ER+ Basal and luminal B cancers. Enrichment analysis between luminal B H1 and H2 cancers showed H2 cancers had higher immune activation and cell proliferation and lower estrogen response. Conclusions: Reclassification by BP of IHC defined ER+ HER2- cancers identified a subgroup of ER+ cancers that are biologically closer to ER- Basal than luminal-type cancers. Significant differences in response to neoadjuvant chemotherapy that have been seen between ER+ Basal and luminal B breast cancers lend support to the clinical importance of these findings. These data explain the poor prognosis observed in patients with ER+ Basal cancers and suggest that optimized chemotherapy, such as that for triple negative cancer, might be of benefit. BP provides clinically actionable information beyond pathological subtyping, which may guide neoadjuvant treatment recommendations. Clinical trial information: NCT03053193.

Short Preoperative Treatment With Erlotinib Inhibits Tumor Cell Proliferation in Hormone Receptor–Positive Breast Cancers

2008 ◽  
Vol 26 (6) ◽  
pp. 897-906 ◽  
Author(s):  
Marta Guix ◽  
Nara de Matos Granja ◽  
Ingrid Meszoely ◽  
Theresa B. Adkins ◽  
Bobbye M. Wieman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Tumor Cell ◽  
Growth Factor Receptor ◽  
Preoperative Treatment ◽  
Breast Cancers ◽  
Tumor Cell Proliferation ◽  
Hormone Receptor Positive ◽  
Er Positive ◽  
Her 2

Purpose To administer the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib to patients with operable untreated breast cancer during the immediate preoperative period and to measure an antiproliferative and/or a proapoptotic effect in the post-therapy specimen and determine a biomarker profile associated with evidence of erlotinib-mediated cellular activity. Patients and Methods Newly diagnosed patients with stages I to IIIA invasive breast cancer were treated with erlotinib 150 mg/d orally for 6 to 14 days until the day before surgery. Erlotinib plasma levels were measured by tandem mass spectrometry the day of surgery. Drug-induced changes in tumor cell proliferation and apoptosis were assessed by Ki67 immunohistochemistry and terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate-biotin nick-end labeling analysis, respectively, in biopsies from the pretherapy and surgical specimens. Biopsies were also evaluated for P-EGFR, P-HER-2, P-MAPK, P-Akt, P-S6, and S118 P-ERα. Results In drug-sensitive PC9 xenografts, 5 days of treatment with erlotinib were enough to induce a maximal inhibition of cell proliferation and induction of apoptosis. Forty-one patients completed preoperative treatment with erlotinib. Grade ≤ 2 rash and diarrhea were the main toxicities. Erlotinib inhibited tumor cell proliferation (Ki67), P-EGFR, and P-HER-2. The inhibition of proliferation occurred in estrogen receptor (ER) –positive but not in human epidermal growth factor receptor 2 (HER-2) –positive or triple-negative cancers. Treatment was associated with a significant reduction of P-MAPK, P-Akt, P-S6, and S118 P-ERα in hormone receptor–positive cancers. Conclusion A presurgical approach to evaluate cellular responses to new drugs is feasible in breast cancer. EGFR inhibitors are worthy of testing against ER-positive breast cancers but are unlikely to have clinical activity against HER-2–positive or triple-negative breast cancers.

scholarly journals Ribavirin Treatment Effects on Breast Cancers Overexpressing eIF4E, a Biomarker with Prognostic Specificity for Luminal B-Type Breast Cancer

2011 ◽  
Vol 17 (9) ◽  
pp. 2874-2884 ◽  
Author(s):  
Filippa Pettersson ◽  
Christina Yau ◽  
Monica C. Dobocan ◽  
Biljana Culjkovic-Kraljacic ◽  
Hélène Retrouvay ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Treatment Effects ◽  
Breast Cancers ◽  
Luminal B

scholarly journals Ki67 index in intrinsic breast cancer subtypes and its association with prognostic parameters

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Atif Ali Hashmi ◽  
Kashif Ali Hashmi ◽  
Muhammad Irfan ◽  
Saadia Mehmood Khan ◽  
Muhammad Muzzammil Edhi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ductal Carcinoma ◽  
Prognostic Significance ◽  
Breast Cancer Subtypes ◽  
Prognostic Parameters ◽  
Ki67 Index ◽  
Breast Cancers ◽  
Cancer Subtypes ◽  
Luminal B ◽  
Cancer Management

Abstract Objectives Ki67 is the most commonly used marker to evaluate proliferative index in breast cancer, however no cutoff values have been clearly defined for high ki67 index. Cancer management should be according to loco-regional profile; therefore, we aimed to determine ki67 index in 1951 cases of intrinsic breast cancer subtypes and its association with other prognostic parameters in our set up. Results Triple negative breast cancers showed highest ki67 index (mean 50.9 ± 23.7%) followed by Her2neu (mean 42.6 ± 21.6%) and luminal B cancers (mean 34.9 ± 20.05%). Metaplastic and medullary breast cancers significantly showed higher ki67 index as compared to ductal carcinoma, NOS. No significant association of ki67 index was noted with any of the histologic parameters in different subtypes of breast cancer expect for tumor grade. Although, ki67 index is a valuable biomarker in breast cancer, however no independent prognostic significance of ki67 could be established in our study.

Basal-like Breast Cancer—Characteristics, Risks, and Associations

2012 ◽  
Vol 08 (01) ◽  
pp. 26
Author(s):  
Andrew Y Shuen ◽  
William D Foulkes ◽  
◽  
Keyword(s):  
Breast Cancer ◽  
Massively Parallel Sequencing ◽  
Target Identification ◽  
Response To Therapy ◽  
Breast Cancers ◽  
Luminal A ◽  
Luminal B ◽  
Predictors Of Response ◽  
Epidemiological Risk ◽  
Basal Like Breast Cancer

Breast cancer is a heterogeneous disease. Gene expression profiling has demonstrated the existence of at least five ‘intrinsic’ subtypes: luminal A, luminal B, human epidermal growth factor-2 receptor (HER2), normal-like, and basal-like. While the estrogen receptor (ER), progesterone receptor (PR), and HER2 remain the most important prognostic markers and predictors of response to therapy, interrogating thousands of genetic transcripts more accurately captures the biological complexity and clinical heterogeneity of this disease. Target identification through massively parallel sequencing is likely to bear fruit in the coming years. Attention to basal-like breast cancers has grown substantially due to their generally poor prognosis, lack of targeted therapies, and connection withBRCA1-related cancers. In this article, we discuss the basal-like subgroup with respect to its cellular origins, relationship toBRCA1, and associated epidemiological risk factors.

scholarly journals DUOX1 Silencing in Mammary Cell Alters the Response to Genotoxic Stress

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Rodrigo S. Fortunato ◽  
Luciana R. Gomes ◽  
Veridiana Munford ◽  
Carolina Fittipaldi Pessoa ◽  
Annabel Quinet ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cellular Proliferation ◽  
Genotoxic Stress ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Adhesion Properties ◽  
Hormone Synthesis ◽  
Wide Range ◽  
Liver Cancers

DUOX1 is an H2O2-generating enzyme related to a wide range of biological features, such as hormone synthesis, host defense, cellular proliferation, and fertilization. DUOX1 is frequently downregulated in lung and liver cancers, suggesting a tumor suppressor role for this enzyme. Here, we show that DUOX1 expression is decreased in breast cancer cell lines and also in breast cancers when compared to the nontumor counterpart. In order to address the role of DUOX1 in breast cells, we stably knocked down the expression of DUOX1 in nontumor mammary cells (MCF12A) with shRNA. This led to higher cell proliferation rates and decreased migration and adhesion properties, which are typical features for transformed cells. After genotoxic stress induced by doxorubicin, DUOX1-silenced cells showed reduced IL-6 and IL-8 secretion and increased apoptosis levels. Furthermore, the cell proliferation rate was higher in DUOX1-silenced cells after doxorubicin medication in comparison to control cells. In conclusion, we demonstrate here that DUOX1 is silenced in breast cancer, which seems to be involved in breast carcinogenesis.

scholarly journals ER, PR, HER2, Ki-67 and CK5 in Early and Late Relapsing Breast Cancer—Reduced CK5 Expression in Metastases

2013 ◽  
Vol 7 ◽  
pp. BCBCR.S10701 ◽  
Author(s):  
Kristiina Joensuu ◽  
Marjut Leidenius ◽  
Mia Kero ◽  
Leif C. Andersson ◽  
Kathryn B. Horwitz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Triple Negative ◽  
Significant Risk ◽  
Growth Factor Receptor ◽  
Primary Therapy ◽  
Breast Cancers ◽  
Luminal A ◽  
Ki 67 ◽  
Luminal B

Breast cancer can recur even decades after the primary therapy. Markers are needed to predict cancer progression and the risk of late recurrence. The estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER2), proliferation marker Ki-67, and cytokeratin CK5 were studied to find out whether their expression or occurrence in subgroups of breast cancers correlated with the time of recurrence. The expression of HER2, ER, PR, Ki-67, and CK5 was studied by IHC in 72 primary breast cancers and their corresponding recurrent/metastatic lesions. The patients were divided into three groups according to the time of the recurrence/metastasis: before two years, after 5 years, and after 10 years. Based on their IHC profiles, the tumors were divided into surrogates of the genetically defined subgroups of breast cancers and the subtype definitions were as follows: luminal A (ER or PR+HER2–), luminal B (ER or PR+HER2+), HER2 overexpressing (ER–PR–HER2+), triple-negative (ER–PR–HER2–), basal-like (ER–PR–HER2–CK5+), non-classified (ER–PR–HER2–CK5–) and luminobasal (ER or PR+CK5+). In multivariate analysis, tumor size and HER2 positivity were a significant risk of early cancer relapse. The metastases showed a significantly lower CK5 expression. CK5 positivity distinguished triple negative tumors into rapidly and slowly recurring cancers. The IHC subtype ER or PR+HER2– luminal A presented a significantly lower risk of early tumor recurrence. Ki-67 expression denoted early-relapsing tumors and correlated linearly with tumor progression, since Ki-67 positivity declined gradually from early-relapsing toward late-recurring cancers.

scholarly journals Evaluation of FGFR targeting in breast cancer through interrogation of patient-derived models

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Nicole J. Chew ◽  
Terry C. C. Lim Kam Sian ◽  
Elizabeth V. Nguyen ◽  
Sung-Young Shin ◽  
Jessica Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Therapeutic Target ◽  
Breast Cancer Subtype ◽  
Breast Cancer Subtypes ◽  
Cancer Tissue ◽  
Breast Cancers ◽  
Luminal A ◽  
Tissue Samples ◽  
Cancer Subtypes ◽  
Luminal B

Abstract Background Particular breast cancer subtypes pose a clinical challenge due to limited targeted therapeutic options and/or poor responses to the existing targeted therapies. While cell lines provide useful pre-clinical models, patient-derived xenografts (PDX) and organoids (PDO) provide significant advantages, including maintenance of genetic and phenotypic heterogeneity, 3D architecture and for PDX, tumor–stroma interactions. In this study, we applied an integrated multi-omic approach across panels of breast cancer PDXs and PDOs in order to identify candidate therapeutic targets, with a major focus on specific FGFRs. Methods MS-based phosphoproteomics, RNAseq, WES and Western blotting were used to characterize aberrantly activated protein kinases and effects of specific FGFR inhibitors. PDX and PDO were treated with the selective tyrosine kinase inhibitors AZD4547 (FGFR1-3) and BLU9931 (FGFR4). FGFR4 expression in cancer tissue samples and PDOs was assessed by immunohistochemistry. METABRIC and TCGA datasets were interrogated to identify specific FGFR alterations and their association with breast cancer subtype and patient survival. Results Phosphoproteomic profiling across 18 triple-negative breast cancers (TNBC) and 1 luminal B PDX revealed considerable heterogeneity in kinase activation, but 1/3 of PDX exhibited enhanced phosphorylation of FGFR1, FGFR2 or FGFR4. One TNBC PDX with high FGFR2 activation was exquisitely sensitive to AZD4547. Integrated ‘omic analysis revealed a novel FGFR2-SKI fusion that comprised the majority of FGFR2 joined to the C-terminal region of SKI containing the coiled-coil domains. High FGFR4 phosphorylation characterized a luminal B PDX model and treatment with BLU9931 significantly decreased tumor growth. Phosphoproteomic and transcriptomic analyses confirmed on-target action of the two anti-FGFR drugs and also revealed novel effects on the spliceosome, metabolism and extracellular matrix (AZD4547) and RIG-I-like and NOD-like receptor signaling (BLU9931). Interrogation of public datasets revealed FGFR2 amplification, fusion or mutation in TNBC and other breast cancer subtypes, while FGFR4 overexpression and amplification occurred in all breast cancer subtypes and were associated with poor prognosis. Characterization of a PDO panel identified a luminal A PDO with high FGFR4 expression that was sensitive to BLU9931 treatment, further highlighting FGFR4 as a potential therapeutic target. Conclusions This work highlights how patient-derived models of human breast cancer provide powerful platforms for therapeutic target identification and analysis of drug action, and also the potential of specific FGFRs, including FGFR4, as targets for precision treatment.

scholarly journals Performing Data Mining to Explain the Correlation between the BIRC5 Gene and Prognosis in Breast Cancer Patients

2020 ◽  
Author(s):  
Hong Dongsheng ◽  
Zhang YanFang ◽  
Ye Ziqi ◽  
Chen Jing ◽  
Lu Xiaoyang
Keyword(s):  
Breast Cancer ◽  
Mrna Expression ◽  
Cancer Patients ◽  
Cancer Cell Line ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Luminal A ◽  
Luminal B ◽  
Kaplan Meier ◽  
Er Positive

Abstract Background: Breast cancer is the most commonly malignant cancers in women, and BIRC5 has been found to be overexpressed in a variety of human tumors. Its expression is associated with the prognosis of many cancers. However, whether BIRC5 mRNA could be used as an independent prognostic factor for breast cancer remains inconsistent in previous studies.Methods: Altered BIRC5 expression in normal tissue relative to various tumor tissue and in breast cancer patients with different molecular subtypes, clinical outcomes and chemotherapy responses were examined using the Oncomine, GOBO and Kaplan-Meier plotter datasets.Results: We found that many breast cancers had increased BIRC5 mRNA expression, and GOBO analysis showed that triple-negative cell lines displayed highest BIRC5 mRNA expression levels in the breast cancer cell line panel. Moreover, BIRC5 high mRNA expression was significantly associated with longer relapse-free survival (RFS) in all breast cancer patients. In particular, sub analysis revealed that high mRNA expression of BIRC5 was significantly associated with better survival in ER positive (HR = 2.05, p = 1e-16), but not in ER negative breast cancer (HR = 1.24, p = 0.1), furthermore, the results also demonstrated that BIRC5 high expression was significantly associated with longer RFS in luminal A (HR = 1.51, p = 3.1e-06) and luminal B (HR = 1.28, p = 0.026).Conclusions: In conclusion, BIRC5 is involved in the development and progression of breast cancer and may be a suitable prognostic marker for human breast cancer.

scholarly journals Characterizing the Relapse Potential in Different Luminal Subtypes of Breast Cancers with Functional Proteomics

2020 ◽  
Vol 21 (17) ◽  
pp. 6077
Author(s):  
Tung-Yi Lin ◽  
Pei-Wen Wang ◽  
Chun-Hsun Huang ◽  
Pei-Ming Yang ◽  
Tai-Long Pan
Keyword(s):  
Breast Cancer ◽  
Cathepsin D ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Term Survival ◽  
Luminal B ◽  
Functional Roles ◽  
The Matrix

Poor prognosis due to the high relapse and metastasis rates of breast cancer has been particularly linked to the luminal B subtype. The current study utilized MCF-7 and ZR-75-1 to investigate various luminal subtypes of breast cancers that have discrepant expressions in the estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2). Understanding of the differential protein profiles and the associated pathways could help alleviate the malignance and promote the long-term survival rate of breast cancer patients. Functional proteome tools were applied to comprehensively delineate the global protein alterations that reflect the varieties of biological features between the two subtypes. In this study, a total of 11 proteins with significant and meaningful changes were identified. These protein targets including PRX2, CK19, nucleophosmin and cathepsin D were mostly involved in cell differentiation or proliferation. Particularly, cathepsin D was highly expressed in the luminal B subtype. Moreover, the level of cathepsin-D was also upregulated in the clinical metastatic tissues. Accordingly, the RNA interference-mediated silencing of cathepsin D stimulated ER expression but suppressed the level of HER2. The knockdown of cathepsin D enhanced the level of ZO-1 and a remarkable decrease in N-cadherin was also detected. Again, the matrix metalloproteinases (MMP) activity was impaired under the cathepsin D abolishment. Collectively, this study represented a modality to explore novel relationships in a proteome complex and highlighted the functional roles of cathepsin D in treatment options for different subtypes of breast cancer.

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