scholarly journals Efficacy of Resveratrol Against Advanced Breast Cancer-Derived Organoids: A comparison with that of Clinically Relevant Drugs

2021 ◽  
Author(s):  
Hai-Shan Ye ◽  
Hong-Fei Gao ◽  
Hong Li ◽  
Jun-Hua Nie ◽  
Ting-Ting Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Nuclear Translocation ◽  
Ex Vivo ◽  
Expression Patterns ◽  
Close Correlation ◽  
Advanced Breast ◽  
Blue Staining ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Surgical Specimen

Abstract Background: The lack of reliable drugs is a therapeutic challenge of advanced breast cancers (ABCs). Resveratrol (Res) exerts inhibitory effects on breast cancer cell lines and animal models, while its efficacy against individual breast cancer cases remain unknown. This study aims to address this issues using ABC-derived organoids (ABCOs) as the ex vivo therapeutic model. Methods: The ABCOs derived from 24 ABC patients were treated with 100 mM resveratrol for 96 hours. Paclitaxel, gemcitabine and fulvestrant were cited as the efficacy controls. Trypan blue staining and Calcein-AM/PI double staining were conducted to elucidate the cell viability, and EdU proliferation assay to evaluate ABCO growth activity. Reactive oxygen species (ROS) levels in Res-treated ABCOs were determined by peroxide-dependent DCFH-DA oxidation assay and the statuses of pSTAT3-mediated signaling was examined by immunofluorescent and immunohistochemical labeling. Results: ABCOs were established from 6 surgical specimen, 14 needle biopsies, 3 cancerous pleural effusion and 1 cancerous ascites. Immunohischemical staining confirmed that the ABCOs maintained ER, PR, HER2 and Ki67 expression patterns of their original tumors. ABCO proliferation and viability tests showed > 50% cell death rates in 79.2% (19/24) of Res-treated, 28.6% (2/7) fulvestrant-treated, 66.7% (4/6) paclitaxel-treated and 66.7% (6/9) gemcitabine-treated ABCOs. The increased ROS levels were found in Res-sensitive ABCOs. pSTAT3 nuclear translocation were more frequent in Res-sensitive (14/19; 73.7%) than that (1/5; 20%) of Res-insensitive ABCOs, which were suppressed upon Res treatment. Statistical analysis revealed close correlation of STAT3 activation with the efficacy of Res.Conclusions: We demonstrate for the first time the effectiveness and broader range of Res against different subtypes of ABCOs in comparison with that of conventional anti-breast cancer drugs, providing an alternative approach for better management of breast cancers, especially those at advanced stage.

scholarly journals HER2 Nuclear Translocation and Decreased T-DM1 Efficacy in HER2 Positive Advanced Breast Cancer Treated with Dual HER2 Blockade. The SePHER Study.

2020 ◽  
Author(s):  
Giulia Bon ◽  
Laura Pizzuti ◽  
Valentina Laquintana ◽  
Rossella Loria ◽  
Manuela Porru ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Nuclear Translocation ◽  
Cancer Cell Lines ◽  
Advanced Breast ◽  
Breast Cancer Cell Lines ◽  
Second Line

Abstract Background: ErbB2-targeting agents have dramatically changed the therapeutic landscape of ErbB2+ advanced breast cancer (ABC). However, their optimal sequence of administration deserves further investigation.Methods: The biology of ErbB2 was investigated through sequential treatments in vitro, in ErbB2+ breast cancer cell lines resistant to trastuzumab, pertuzumab, and their combination. We analyzed data from 555 ErbB2+ ABC patients treated with trastuzumab emtansine (T-DM1) and explored the efficacy of T-DM1 in the 371 patients who received it in second-line. Survival estimates were graphically displayed in Kaplan Meier curves, compared by log rank test and, when possibile, confirmed in multivariate models.Results: We show here lower activity of T-DM1 in two HER2+ breast cancer cell lines resistant to trastuzumab+pertuzumab, as compared to trastuzumab-resistant cells. Reduced T-DM1 efficacy is associated with a marked reduction of HER2 expression on the cell membrane and its nuclear translocation. Membrane-HER2 downregulation was confirmed in biopsies of four trastuzumab/pertuzumab-pretreated patients. Among 371 patients treated with second-line T-DM1, median overall survival (mOS) from diagnosis and median progression-free survival to second-line treatment (mPFS2) were 52 and 6 months in 177 patients who received trastuzumab/pertuzumab in first-line, and 74 and 10 months in 194 pertuzumab-naïve patients (p=0.0006 and 0.03 for OS and PFS2, respectively). Conclusions: Our data support the hypothesis that the addition of pertuzumab to trastuzumab reduces the amount of available plasma membrane HER2 receptor, limiting the binding of T-DM1 to cancer cells. This may help interpret the less favorable outcomes of second-line T-DM1 in trastuzumab/pertuzumab pre-treated patients compared to their pertuzumab-naïve counterpart.

scholarly journals Nicardipine Inhibits Breast Cancer Migration via Nrf2/HO-1 Axis and Matrix Metalloproteinase-9 Regulation

2021 ◽  
Vol 12 ◽  
Author(s):  
Yen-Chang Chen ◽  
Jia-Hong Chen ◽  
Cheng-Fang Tsai ◽  
Chen-Teng Wu ◽  
Miao-Hsiang Wu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Matrix Metalloproteinase ◽  
Calcium Channel ◽  
Matrix Metalloproteinase 9 ◽  
Advanced Breast ◽  
Breast Cancer Cell Lines ◽  
Potential Candidate ◽  
Breast Cancers ◽  
End Products ◽  
Metalloproteinase 9

Background: Metastasis represents an advanced stage of cancers, and matrix metalloproteinases are critical regulators. Calcium signal is crucial for appropriate cell behaviors. The efficacy and effects of calcium channel blockers in treating cancers are individually differ from each other. Here, we attempt to investigate the effects of nicardipine, a FDA-approved calcium channel blocker, in advanced breast cancers.Methods: We analyzed the influence of nicardipine on the colony-forming ability of triple negative breast cancer cell lines. Using cell culture inserts, cell migration was also examined. The expression of regulatory proteins was evaluated by real-time PCR, Western blot, and ELISA.Results: We have confirmed that nicardipine inhibits the breast cancer cells migration and colony formation. In addition, we also revealed that nicardipine increases the Nrf2 and HO-1 expression. The inhibition of HO-1 abrogates nicardipine-reduced matrix metalloproteinase-9 expression. Moreover, the end products of HO-1, namely, CO, Fe2+, and biliverdin (will converted to bilirubin), also decreases the expression of matrix metalloproteinase-9.Conclusion: These findings suggest that nicardipine-mediated matrix metalloproteinase-9 reduction is regulated by Nrf2/HO-1 axis and its catalytic end products. Therefore, nicardipine may be a potential candidate for repurposing against advanced breast cancers.

scholarly journals LPTO-06. A NOVEL BRAIN-PERMEANT CHEMOTHERAPEUTIC AGENT FOR THE TREATMENT OF BREAST CANCER LEPTOMENINGEAL METASTASIS

2019 ◽  
Vol 1 (Supplement_1) ◽  
pp. i7-i7
Author(s):  
Jiaojiao Deng ◽  
Sophia Chernikova ◽  
Wolf-Nicolas Fischer ◽  
Kerry Koller ◽  
Bernd Jandeleit ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Tumors ◽  
Cell Lines ◽  
Chemotherapeutic Agent ◽  
Leptomeningeal Metastasis ◽  
Breast Cancer Cell Lines ◽  
Normal Brain ◽  
Breast Cancers

Abstract Leptomeningeal metastasis (LM), a spread of cancer to the cerebrospinal fluid and meninges, is universally and rapidly fatal due to poor detection and no effective treatment. Breast cancers account for a majority of LMs from solid tumors, with triple-negative breast cancers (TNBCs) having the highest propensity to metastasize to LM. The treatment of LM is challenged by poor drug penetration into CNS and high neurotoxicity. Therefore, there is an urgent need for new modalities and targeted therapies able to overcome the limitations of current treatment options. Quadriga has discovered a novel, brain-permeant chemotherapeutic agent that is currently in development as a potential treatment for glioblastoma (GBM). The compound is active in suppressing the growth of GBM tumor cell lines implanted into the brain. Radiolabel distribution studies have shown significant tumor accumulation in intracranial brain tumors while sparing the adjacent normal brain tissue. Recently, we have demonstrated dose-dependent in vitro and in vivo anti-tumor activity with various breast cancer cell lines including the human TNBC cell line MDA-MB-231. To evaluate the in vivo antitumor activity of the compound on LM, we used the mouse model of LM based on the internal carotid injection of luciferase-expressing MDA-MB-231-BR3 cells. Once the bioluminescence signal intensity from the metastatic spread reached (0.2 - 0.5) x 106 photons/sec, mice were dosed i.p. twice a week with either 4 or 8 mg/kg for nine weeks. Tumor growth was monitored by bioluminescence. The compound was well tolerated and caused a significant delay in metastatic growth resulting in significant extension of survival. Tumors regressed completely in ~ 28 % of treated animals. Given that current treatments for LM are palliative with only few studies reporting a survival benefit, Quadriga’s new agent could be effective as a therapeutic for both primary and metastatic brain tumors such as LM. REF: https://onlinelibrary.wiley.com/doi/full/10.1002/pro6.43

scholarly journals MRCKα Is Dispensable for Breast Cancer Development in the MMTV-PyMT Model

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 942
Author(s):  
Mei Qi Kwa ◽  
Rafael Brandao ◽  
Trong H. Phung ◽  
Jianfeng Ge ◽  
Giuseppe Scieri ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression Signature ◽  
Genomic Analysis ◽  
Cancer Development ◽  
Breast Cancer Cell Lines ◽  
Normal Mammary Gland ◽  
Breast Cancers ◽  
Human Breast ◽  
Breast Cancer Development

MRCKα is a ubiquitously expressed serine/threonine kinase involved in cell contraction and F-actin turnover, which is highly amplified in human breast cancer and part of a gene expression signature for bad prognosis. Nothing is known about the in vivo function of MRCKα. To explore MRCKα function in development and in breast cancer, we generated mice lacking a functional MRCKα gene. Mice were born close to the Mendelian ratio and showed no obvious phenotype including a normal mammary gland formation. Assessing breast cancer development using the transgenic MMTV-PyMT mouse model, loss of MRCKα did not affect tumor onset, tumor growth and metastasis formation. Deleting MRCKα and its related family member MRCKβ in two triple-negative breast cancer cell lines resulted in reduced invasion of MDA-MB-231 cells, but did not affect migration of 4T1 cells. Further genomic analysis of human breast cancers revealed that MRCKα is frequently co-amplified with the oncogenes ARID4B and AKT3 which might contribute to the prognostic value of MRCKα expression. Collectively, these data suggest that MRCKα might be a prognostic marker for breast cancer, but probably of limited functional importance.

scholarly journals Extracellular Calcium-Sensing Receptor Expression and Its Potential Role in Regulating Parathyroid Hormone-Related Peptide Secretion in Human Breast Cancer Cell Lines*

Endocrinology ◽  
2000 ◽  
Vol 141 (12) ◽  
pp. 4357-4364 ◽  
Author(s):  
Jennifer L. Sanders ◽  
Naibedya Chattopadhyay ◽  
Olga Kifor ◽  
Toru Yamaguchi ◽  
Robert R. Butters ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Human Breast Cancer ◽  
Cancer Cell Lines ◽  
Human Breast Cancer Cell ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Human Breast

Abstract Metastasis of breast cancer to bone occurs with advanced disease and produces substantial morbidity. Secretion of PTH-related peptide (PTHrP) from breast cancer cells is thought to play a key role in osteolytic metastases and is increased by transforming growth factor-β (TGFβ), which is released from resorbed bone. Elevated extracellular calcium (Cao2+) also stimulates PTHrP secretion from various normal and malignant cells, an action that could potentially be mediated by the Cao2+-sensing receptor (CaR) originally cloned from the parathyroid gland. Indeed, we previously showed that both normal breast ductal epithelial cells and primary breast cancers express the CaR. In this study we investigated whether the MCF-7 and MDA-MB-231 human breast cancer cell lines express the CaR and whether CaR agonists modulate PTHrP secretion. Northern blot analysis and RT-PCR revealed bona fide CaR transcripts, and immunocytochemistry and Western analysis with a specific anti-CaR antiserum demonstrated CaR protein expression in both breast cancer cell lines. Furthermore, elevated Cao2+ and the polycationic CaR agonists, neomycin and spermine, stimulated PTHrP secretion dose dependently, with maximal, 2.1- to 2.3-fold stimulation. In addition, pretreatment of MDA-MB-231 cells overnight with TGFβ1 (0.2, 1, or 5 ng/ml) augmented both basal and high Cao2+-stimulated PTHrP secretion. Thus, in PTHrP-secreting breast cancers metastatic to bone, the CaR could potentially participate in a vicious cycle in which PTHrP-induced bone resorption raises the levels of Cao2+ and TGFβ within the bony microenvironment, which then act in concert to evoke further PTHrP release and worsening osteolysis.

scholarly journals Inhibition of Histone Demethylases LSD1 and UTX Regulates ERα Signaling in Breast Cancer

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 2027 ◽  
Author(s):  
Rosaria Benedetti ◽  
Carmela Dell’Aversana ◽  
Tommaso De Marchi ◽  
Dante Rotili ◽  
Ning Qing Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Histone Methylation ◽  
Ex Vivo ◽  
Acquired Resistance ◽  
Chemical Properties ◽  
Breast Cancers ◽  
Histone Demethylases ◽  
Lysine Specific Demethylase ◽  
Breast Cancer Model

In breast cancer, Lysine-specific demethylase-1 (LSD1) and other lysine demethylases (KDMs), such as Lysine-specific demethylase 6A also known as Ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX), are co-expressed and co-localize with estrogen receptors (ERs), suggesting the potential use of hybrid (epi)molecules to target histone methylation and therefore regulate/redirect hormone receptor signaling. Here, we report on the biological activity of a dual-KDM inhibitor (MC3324), obtained by coupling the chemical properties of tranylcypromine, a known LSD1 inhibitor, with the 2OG competitive moiety developed for JmjC inhibition. MC3324 displays unique features not exhibited by the single moieties and well-characterized mono-pharmacological inhibitors. Inhibiting LSD1 and UTX, MC3324 induces significant growth arrest and apoptosis in hormone-responsive breast cancer model accompanied by a robust increase in H3K4me2 and H3K27me3. MC3324 down-regulates ERα in breast cancer at both transcriptional and non-transcriptional levels, mimicking the action of a selective endocrine receptor disruptor. MC3324 alters the histone methylation of ERα-regulated promoters, thereby affecting the transcription of genes involved in cell surveillance, hormone response, and death. MC3324 reduces cell proliferation in ex vivo breast cancers, as well as in breast models with acquired resistance to endocrine therapies. Similarly, MC3324 displays tumor-selective potential in vivo, in both xenograft mice and chicken embryo models, with no toxicity and good oral efficacy. This epigenetic multi-target approach is effective and may overcome potential mechanism(s) of resistance in breast cancer.

scholarly journals Currently Applied Molecular Assays for Identifying ESR1 Mutations in Patients with Advanced Breast Cancer

2020 ◽  
Vol 21 (22) ◽  
pp. 8807
Author(s):  
Nuri Lee ◽  
Min-Jeong Park ◽  
Wonkeun Song ◽  
Kibum Jeon ◽  
Seri Jeong
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Endocrine Therapy ◽  
High Sensitivity ◽  
Digital Pcr ◽  
Advanced Breast ◽  
Sample Type ◽  
Breast Cancers ◽  
Esr1 Mutations ◽  
Next Generation Sequencing Ngs

Approximately 70% of breast cancers, the leading cause of cancer-related mortality worldwide, are positive for the estrogen receptor (ER). Treatment of patients with luminal subtypes is mainly based on endocrine therapy. However, ER positivity is reduced and ESR1 mutations play an important role in resistance to endocrine therapy, leading to advanced breast cancer. Various methodologies for the detection of ESR1 mutations have been developed, and the most commonly used method is next-generation sequencing (NGS)-based assays (50.0%) followed by droplet digital PCR (ddPCR) (45.5%). Regarding the sample type, tissue (50.0%) was more frequently used than plasma (27.3%). However, plasma (46.2%) became the most used method in 2016–2019, in contrast to 2012–2015 (22.2%). In 2016–2019, ddPCR (61.5%), rather than NGS (30.8%), became a more popular method than it was in 2012–2015. The easy accessibility, non-invasiveness, and demonstrated usefulness with high sensitivity of ddPCR using plasma have changed the trends. When using these assays, there should be a comprehensive understanding of the principles, advantages, vulnerability, and precautions for interpretation. In the future, advanced NGS platforms and modified ddPCR will benefit patients by facilitating treatment decisions efficiently based on information regarding ESR1 mutations.

Molecular Testing in Breast Cancer

2019 ◽  
pp. e1-e7 ◽  
Author(s):  
Jennifer K. Litton ◽  
Harold J. Burstein ◽  
Nicholas C. Turner
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Hereditary Cancer ◽  
Standard Of Care ◽  
Genomic Variation ◽  
Advanced Breast ◽  
Hereditary Cancer Syndrome ◽  
Molecular Testing ◽  
Breast Cancers ◽  
Cancer Management

Molecular testing for genetic and genomic variation has become an integral part of breast cancer management. Patients with a family history of breast cancer or other tumors, bilateral breast cancers, or early-onset breast cancers warrant genetic testing to determine whether a hereditary cancer syndrome is present. The availability of PARP inhibitors—drugs that are selectively active in BRCA1/2-associated breast cancers—has created the need for hereditary cancer testing for all patients diagnosed with advanced breast cancer. Tumor genomic profiling is the standard of care for many types of malignancies and is becoming increasingly important in the management of advanced breast cancer. Targetable mutations in advanced breast cancer include PIK3CA, HER2, and rare instances of mismatch deficiency or other targets for tyrosine kinase inhibitors. The development of methods for sequencing cell-free DNA should allow for broader and easier implementation of tumor genomic testing. Transcriptome-based expression signatures have become the standard of care in the management of early-stage estrogen receptor–positive breast cancers. These assays provide prognostic significance in the setting of adjuvant endocrine therapy and are predictive for benefit from adjuvant chemotherapy. Collectively, these developments underscore the contemporary reality that molecular testing is now part of the clinical management for the majority of patients with breast cancer.

scholarly journals Selective Effects of Thioridazine on Self-Renewal of Basal-Like Breast Cancer Cells

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Matthew Tegowski ◽  
Cheng Fan ◽  
Albert S. Baldwin
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cells ◽  
Cell Types ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Self Renewal ◽  
Basal Like Breast Cancer

AbstractSeveral recent publications demonstrated that DRD2-targeting antipsychotics such as thioridazine induce proliferation arrest and apoptosis in diverse cancer cell types including those derived from brain, lung, colon, and breast. While most studies show that 10–20 µM thioridazine leads to reduced proliferation or increased apoptosis, here we show that lower doses of thioridazine (1–2 µM) target the self-renewal of basal-like breast cancer cells, but not breast cancer cells of other subtypes. We also show that all breast cancer cell lines tested express DRD2 mRNA and protein, regardless of thioridazine sensitivity. Further, DRD2 stimulation with quinpirole, a DRD2 agonist, promotes self-renewal, even in cell lines in which thioridazine does not inhibit self-renewal. This suggests that DRD2 is capable of promoting self-renewal in these cell lines, but that it is not active. Further, we show that dopamine can be detected in human and mouse breast tumor samples. This observation suggests that dopamine receptors may be activated in breast cancers, and is the first time to our knowledge that dopamine has been directly detected in human breast tumors, which could inform future investigation into DRD2 as a therapeutic target for breast cancer.

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