scholarly journals Celastrol and Triptolide Suppress Stemness in Triple Negative Breast Cancer: Notch as a Therapeutic Target for Stem Cells

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 482
Author(s):  
Prabhu Ramamoorthy ◽  
Prasad Dandawate ◽  
Roy A. Jensen ◽  
Shrikant Anant
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Notch Signaling ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Critical Role ◽  
Distant Metastases ◽  
Stem Cell Marker ◽  
Breast Cancers ◽  
Mammosphere Formation

Triple negative breast cancer (TNBC) is observed in ~15% of breast cancers and results in poor survival and increased distant metastases. Within the tumor are present a small portion of cancer stem cells that drive tumorigenesis and metastasis. In this study, we aimed to elucidate whether the two natural compounds, celastrol and triptolide, inhibit stemness in TNBC. MDA-MB-231, BT20, and a patient-derived primary cells (PD-TNBC) were used in the study. Mammosphere assay was performed to assess the stemness. Both celastrol and triptolide treatment suppressed mammosphere formation. Furthermore, the compound suppressed expression of cancer stem cell marker proteins DCLK1, ALDH1, and CD133. Notch signaling plays a critical role in stem cells renewal. Both celastrol or triptolide reduced Notch -1 activation and expression of its downstream target proteins HES-1 and HEY-1. However, when NICD 1 was ectopically overexpressed in the cells, it partially rescued proliferation and mammosphere formation of the cells, supporting the role of notch signaling. Together, these data demonstrate that targeting stem cells and the notch signaling pathway may be an effective strategy for curtailing TNBC progression.

Beyond triple-negative breast cancer and African ancestry: Tumor phenotypes among internationally diverse patient populations.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1101-1101
Author(s):  
Evelyn Mawunyo Jiagge ◽  
Aisha Jibril ◽  
George Divine ◽  
Kofi K. Gyan ◽  
Jessica Miley Bensenhaver ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
African Ancestry ◽  
West African ◽  
Stem Cell Marker ◽  
Breast Cancers ◽  
East African ◽  
Increased Risk ◽  
West African Ancestry

1101 Background: Population-based incidence rates of breast cancers that are negative for estrogen receptor (ER), progesterone receptor (PR), and HER2/ neu(triple negative breast cancer {TNBC}) are higher among African American (AA) compared to White American (WA) women. Several studies show higher TNBC frequency among selected populations of African patients. The colonial-era trans-Atlantic slave trade resulted in shared West African ancestry between contemporary AA and Ghanaian (Gh) populations. The extent to which TNBC susceptibility is related to East African versus West African ancestry, and whether these associations extend to expression of other biomarkers such as Androgen Receptor (AR) and mammary stem cell marker ALDH1 is unknown. Methods: We used immunohistochemistry to assess ER, PR, HER2/ neu, AR and ALDH1 among WA (n = 153); AA (n = 76); Ethiopian (Eth)/East African (n = 90) and (Gh)/West African (n = 286) breast cancers through an IRB-approved international research program. Results: Mean age at breast cancer diagnosis was 43; 49; 60; and 57 years for the Eth; Gh; AA; and WA patients, respectively. Frequency of TNBC was significantly higher for AA and Gh patients (54% and 41%, respectively) compared to WA and Eth patients (23% and 15%, respectively); p < 0.001. These associations were unchanged when limited to patients age 50 and younger (47% and 49% for AA and Gh, respectively; versus 18% and 16% for WA and Eth, respectively); p < 0.001. Frequency of ALDH1 positivity was also higher for tumors from AA and Gh patients (32% and 36%, respectively) compared to those from WA and Eth patients (23% and 17%, respectively); p = 0.007. Significant differences were observed for distribution of AR positivity, which was 71%; 55%; 42% and 50% for the WA; AA; Gh; and Eth cases, respectively (p = 0.008). Conclusions: We found a correlation between extent of African ancestry and risk of particular BC phenotypes. West African ancestry was associated with increased risk of TNBC and breast cancers that are positive for ALDH1. Future studies of hereditary TNBC susceptibility among women with African ancestry are warranted.

scholarly journals LncRNA PART1 Promotes Proliferation and Migration, Is Associated with Cancer Stem Cells, and Alters the miRNA Landscape in Triple-Negative Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2644
Author(s):  
Brianne M. Cruickshank ◽  
Marie-Claire D. Wasson ◽  
Justin M. Brown ◽  
Wasundara Fernando ◽  
Jaganathan Venkatesh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Gene Regulation ◽  
Cancer Stem Cells ◽  
Triple Negative ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Mammosphere Formation ◽  
Basal Like Breast Cancer ◽  
Myosin Va

Triple-negative breast cancers (TNBCs) are aggressive, lack targeted therapies and are enriched in cancer stem cells (CSCs). Novel therapies which target CSCs within these tumors would likely lead to improved outcomes for TNBC patients. Long non-coding RNAs (lncRNAs) are potential therapeutic targets for TNBC and CSCs. We demonstrate that lncRNA prostate androgen regulated transcript 1 (PART1) is enriched in TNBCs and in Aldefluorhigh CSCs, and is associated with worse outcomes among basal-like breast cancer patients. Although PART1 is androgen inducible in breast cancer cells, analysis of patient tumors indicates its androgen regulation has minimal clinical impact. Knockdown of PART1 in TNBC cell lines and a patient-derived xenograft decreased cell proliferation, migration, tumor growth, and mammosphere formation potential. Transcriptome analyses revealed that the lncRNA affects expression of hundreds of genes (e.g., myosin-Va, MYO5A; zinc fingers and homeoboxes protein 2, ZHX2). MiRNA 4.0 GeneChip and TaqMan assays identified multiple miRNAs that are regulated by cytoplasmic PART1, including miR-190a-3p, miR-937-5p, miR-22-5p, miR-30b-3p, and miR-6870-5p. We confirmed the novel interaction between PART1 and miR-937-5p. In general, miRNAs altered by PART1 were less abundant than PART1, potentially leading to cell line-specific effects in terms miRNA-PART1 interactions and gene regulation. Together, the altered miRNA landscape induced by PART1 explains most of the protein-coding gene regulation changes (e.g., MYO5A) induced by PART1 in TNBC.

scholarly journals Anti-Cancer Effects of an Optimised Combination of Ginsenoside Rg3 Epimers on Triple Negative Breast Cancer Models

2021 ◽  
Vol 14 (7) ◽  
pp. 633
Author(s):  
Maryam Nakhjavani ◽  
Eric Smith ◽  
Helen M. Palethorpe ◽  
Yoko Tomita ◽  
Kenny Yeo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Primary Tumour ◽  
Stem Cell Marker ◽  
Ginsenoside Rg3 ◽  
Mammosphere Formation ◽  
Nsg Mice ◽  
Inhibitory Function ◽  
Rsm Model

Key problems of chemotherapies, as the mainstay of treatment for triple-negative breast cancer (TNBC), are toxicity and development of tumour resistance. Using response surface methodology, we previously optimised the combination of epimers of ginsenoside Rg3 (Rg3) for anti-angiogenic action. Here, we show that the optimised combination of 50 µM SRg3 and 25 µM RRg3 (C3), derived from an RSM model of migration of TNBC cell line MDA-MB-231, inhibited migration of MDA-MB-231 and HCC1143, in 2D and 3D migration assays (p < 0.0001). C3 inhibited mammosphere formation efficiency in both cell lines and decreased the CD44+ stem cell marker in the mammospheres. Molecular docking predicted that Rg3 epimers had a better binding score with IGF-1R than with EGFR, HER-2 or PDGFR, and predicted an mTOR inhibitory function of Rg3. C3 affected the signalling of AKT in MDA-MB-231 and HCC1143 mammospheres. In a mouse model of metastatic TNBC, an equivalent dose of C3 (23 mg/kg SRg3 + 11 mg/kg RRg3) or an escalated dose of 46 mg/kg SRg3 + 23 mg/kg RRg3 was administered to NSG mice bearing MDA-MB-231-Luc cells. Calliper and IVIS spectrum measurement of the primary and secondary tumour showed that the treatment shrunk the primary tumour and decreased the load of metastasis in mice. In conclusion, this combination of Rg3 epimers showed promising results as a potential treatment option for TNBC patients.

Prevalence of androgen receptors expression in triple negative breast cancer patients and its correlation with clinicopathological criteria: Our institutes experience.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e12584-e12584 ◽  
Author(s):  
Kamel Farag ◽  
Ola Elfarargy ◽  
Shereen El Shorbagy ◽  
Safa Ahmed ◽  
Ola Harb ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Androgen Receptors ◽  
Distant Metastases ◽  
Clinicopathological Parameters ◽  
P Value ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Positive Expression

e12584 Background: Triple negative breast cancer (TNBC) is a term that has been applied to breast cancers which lack expression of three receptors: estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2). It represents about 20% of breast cancers diagnosed worldwide. TNBC is a challenging type by its presentation criteria and limited options of treatment. Continuous research for finding specific target is the aim of scientists. Androgen receptors (AR) expression take special attention in this type of breast cancer as its expression can help for finding special targeted treatment as antiandrogen therapy.Purpose:is to assess the AR expression in TNBC patients and to correlate its expression with clinicopathological parameters and disease outcome of patients in study populations. Methods: This prospective study included 90 female patients confirmed as TNBC patients in medical oncology and clinical oncology departments, in Mansoura University and Zagazig University, Egypt, between December, 2013 to May, 2016. AR positive expression was defined as ≥10% nuclear immunostaining. Results: AR expression was positive in twenty seven (27/90) patients (30% ), and lack of its expression was significantly associated with younger age group(p < 0.001), higher grade(p = 0.017)& higher tumor stage(p < 0.001), presence of lymph node metastasis(p < 0.001) & distant metastases(p = 0.032), vascular(p = 0.044)& perineural invasion and high baseline CA 15-3 level (p < 0.001).Median follow up duration was 17.5months (range 6-40), 32/90 died (35.6%).Mean OS was 28months for AR negative TNBC patients versus 32months for AR positive patients. Twenty four of died patients (24/32) were AR negative. Three years OS was 50.8% and 44.1% for AR positive and AR negative respectively, but with nonsignificant P-value. Conclusions: Our study confirmed that AR positive expression in TNBC is a good prognostic feature and it can be sued as target for antiandrogen therapy in this group who is lacking any targettreatment.

Id proteins promote a cancer stem cell phenotype in triple negative breast cancer via negative regulation of Robo1

2018 ◽  
Author(s):  
Wee S. Teo ◽  
Holly Holliday ◽  
Nitheesh Karthikeyan ◽  
Aurélie S. Cazet ◽  
Daniel L. Roden ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Negative Regulation ◽  
Breast Cancers ◽  
Self Renewal ◽  
Metastatic Dissemination

AbstractBreast cancers display phenotypic and functional heterogeneity and several lines of evidence support the existence of cancer stem cells (CSCs) in certain breast cancers, a minor population of cells capable of tumor initiation and metastatic dissemination. Identifying factors that regulate the CSC phenotype is therefore important for developing strategies to treat metastatic disease. The Inhibitor of Differentiation Protein 1 (Id1) and its closely related family member Inhibitor of Differentiation 3 (Id3) (collectively termed Id) are expressed by a diversity of stem cells and are required for metastatic dissemination in experimental models of breast cancer. In this study, we show that ID1 is expressed in rare neoplastic cells within ER-negative breast cancers. To address the function of Id1 expressing cells within tumors, we developed two independent murine models of Triple Negative Breast Cancer (TNBC) in which a genetic reporter permitted the prospective isolation of Id1+cells. Id1+cells are enriched for self-renewal in tumorsphere assaysin vitroand for tumor initiationin vivo. Conversely, depletion of Id1 and Id3 in the 4T1 murine model of TNBC demonstrates that Id1/3 are required for cell proliferation and self-renewalin vitro, as well as primary tumor growth and metastatic colonization of the lungin vivo. Using combined bioinformatic analysis, we have defined a novel mechanism of Id protein function via negative regulation of the Roundabout Axon Guidance Receptor Homolog 1 (Robo1) leading to activation of a Myc transcriptional programme.

scholarly journals TrkA Interacts with and Phosphorylates STAT3 to Enhance Gene Transcription and Promote Breast Cancer Stem Cells in Triple-Negative and HER2-Enriched Breast Cancers

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2340
Author(s):  
Angelina T. Regua ◽  
Noah R. Aguayo ◽  
Sara Abu Jalboush ◽  
Daniel L. Doheny ◽  
Sara G. Manore ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Gene Transcription ◽  
Target Genes ◽  
Triple Negative ◽  
Breast Cancer Stem Cells ◽  
Breast Cancers ◽  
Co Activation ◽  
Stat3 Phosphorylation

JAK2–STAT3 and TrkA signaling pathways have been separately implicated in aggressive breast cancers; however, whether they are co-activated or undergo functional interaction has not been thoroughly investigated. Herein we report, for the first time that STAT3 and TrkA are significantly co-overexpressed and co-activated in triple-negative breast cancer (TNBC) and HER2-enriched breast cancer, as shown by immunohistochemical staining and data mining. Through immunofluorescence staining–confocal microscopy and immunoprecipitation–Western blotting, we found that TrkA and STAT3 co-localize and physically interact in the cytoplasm, and the interaction is dependent on STAT3-Y705 phosphorylation. TrkA–STAT3 interaction leads to STAT3 phosphorylation at Y705 by TrkA in breast cancer cells and cell-free kinase assays, indicating that STAT3 is a novel substrate of TrkA. β-NGF-mediated TrkA activation induces TrkA–STAT3 interaction, STAT3 nuclear transport and transcriptional activity, and the expression of STAT3 target genes, SOX2 and MYC. The co-activation of both pathways promotes breast cancer stem cells. Finally, we found that TNBC and HER2-enriched breast cancer with JAK2–STAT3 and TrkA co-activation are positively associated with poor overall metastasis-free and organ-specific metastasis-free survival. Collectively, our study uncovered that TrkA is a novel activating kinase of STAT3, and their co-activation enhances gene transcription and promotes breast cancer stem cells in TNBC and HER2-enriched breast cancer.

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