scholarly journals Notch1 regulates breast cancer stem cell function via a non-canonical cleavage-independent pathway

2020 ◽  
Author(s):  
Lufei Sui ◽  
Suming Wang ◽  
Roberto K. Rodriguez ◽  
Danielle Sim ◽  
Nandita Bhattacharya ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Cancer Stem Cell ◽  
Notch Signaling ◽  
Triple Negative ◽  
Cell Function ◽  
Breast Cancer Stem Cells ◽  
Tumor Initiation

AbstractCurrent treatment of triple negative breast cancer patients is hindered by a high incidence of chemoresistance (30-50%). The prevailing theory is that resistance and subsequent recurrence is driven by cancer stem cells. Unfortunately, the functional characterization of cancer stem cells at the molecular level is still incomplete. We show here, that within the canonical breast cancer stem cell population, a subset of cells characterized by high Notch1 expression possesses the tumor-initiating property associated with cancer stem cells. Moreover, the tumor initiating property of these high Notch1-expressing breast cancer stem cells is mediated by a cleavage independent Notch signaling pathway culminating in the repression of SIRT1. Of note, the Notch1-mediated repression of SIRT1 is required not only for tumor initiation, but also for chemoresistance in breast cancer stem cells. Strikingly, inhibition of SIRT1 obviates the requirement for Notch1, marking the first example of conferring cancer stem cell function by inhibiting the activity of a single protein. We also demonstrate that progenitor-like mammary epithelial cells, which possess both luminal and basal properties, are also characterized by high Notch1 expression and repression of SIRT1 via the non-canonical pathway. These findings provide the first functional mechanistic requirements for tumor initiation by breast cancer stem cells and suggest that activation of the non-canonical Notch1 pathway is hardwired into tumor-initiating progenitor cells and thus a prerequisite for tumor initiation.Statement of SignificanceWe demonstrate that chemoresistant and tumor-initiating properties of breast cancer stem cells are driven by repression of SIRT1 via non-canonical Notch signaling, suggesting a novel therapeutic strategy for triple negative breast cancer.

scholarly journals The Role of Breast Cancer Stem Cells in Chemoresistance and Metastasis in Triple-Negative Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6209
Author(s):  
Lin He ◽  
Neda Wick ◽  
Sharon Koorse Germans ◽  
Yan Peng
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Cancer Stem Cell ◽  
Triple Negative Breast Cancer ◽  
Targeted Therapies ◽  
Triple Negative ◽  
Breast Cancer Stem Cells

Triple negative breast cancer (TNBC) remains an aggressive disease due to the lack of targeted therapies and relatively low rate of response to chemotherapy, which is currently the main treatment modality for TNBC. Breast cancer stem cells (BCSCs) are a small subpopulation of breast tumors and recognized as drivers of tumorigenesis. TNBC tumors are characterized as being enriched for BCSCs. Studies have demonstrated the role of BCSCs as the source of metastatic disease and chemoresistance in TNBC. Multiple targets against BCSCs are now under investigation, with the considerations of either selectively targeting BCSCs or co-targeting BCSCs and non-BCSCs (majority of tumor cells). This review article provides a comprehensive overview of recent advances in the role of BCSCs in TNBC and the identification of cancer stem cell biomarkers, paving the way for the development of new targeted therapies. The review also highlights the resultant discovery of cancer stem cell targets in TNBC and offers summaries of ongoing clinical trials treating chemoresistant breast cancer. We aim to better understand the mutational landscape of BCSCs and explore potential molecular signaling pathways targeting BCSCs to overcome chemoresistance and prevent metastasis in TNBC, ultimately to improve the overall survival of patients with this devastating disease.

scholarly journals A Systematic Review to Clarify the Prognostic Values of CD44 and CD44+CD24- Phenotype in Triple-Negative Breast Cancer Patients: Lessons Learned and The Road Ahead

2021 ◽  
Vol 11 ◽  
Author(s):  
Mahdi Abdoli Shadbad ◽  
Negar Hosseinkhani ◽  
Zahra Asadzadeh ◽  
Afshin Derakhshani ◽  
Noora Karim Ahangar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Cancer Stem Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cell Phenotype ◽  
Stem Cell Markers ◽  
Advanced Tumor Stage

As a unique population of tumor bulk, cancer stem cells have been implicated in tumor relapse and chemoresistance in triple-negative breast cancer (TNBC). Therefore, understanding the phenotype of cancer stem cells can pave the way for introducing novel molecular targeted therapies for treating TNBC patients. Preclinical studies have identified CD44+CD24-/low as a cancer stem cell phenotype; however, clinical studies have reported seemingly controversial results regarding the prognostic values of CD44 and CD44+CD24-/low phenotype in TNBC patients. To critically review the clinicopathological significance and prognostic values of CD44 and CD44+CD24-/low phenotype in TNBC patients, the Scopus, Embase, PubMed, and Web of Science databases were systematically searched to obtain the relevant records published before 20 October 2020. Based on nine included studies, CD44 and CD44+CD24-/low phenotype are associated with inferior prognosis in TNBC patients. Moreover, these cancer stem cell markers have been associated with advanced tumor stage, tumor size, higher tumor grade, tumor metastasis, and lymphatic involvement in TNBC patients. Our evidence has also indicated that, unlike the treatment-naïve TNBC patients, the tumoral cells of chemoradiotherapy-treated TNBC patients can upregulate the CD44+CD24-/low phenotype and establish an inverse association with androgen receptor (AR), leading to the inferior prognosis of affected patients. In summary, CD44 and CD44+CD24-/low phenotype can be utilized to determine TNBC patients’ prognosis in the pathology department as a routine practice, and targeting these phenotypes can substantially improve the prognosis of TNBC patients.

scholarly journals Effect of CD44 knockdown on the biological characteristics of breast cancer stem cells

2020 ◽  
Author(s):  
Zi Lei ◽  
Yang-Li Hu ◽  
Qiang Feng ◽  
Li Wang ◽  
Xin-Yan Pan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Cancer Stem Cell ◽  
Biological Characteristics ◽  
Breast Cancer Stem Cells ◽  
Transcript Variants

Abstract Background: CD44 is an important surface marker of breast cancer stem cells (BCSCs), but it is unclear whether it is involved in the stemness of BCSCs. This has limited the development of new therapeutic strategies for breast cancer. Previous studies have shown that many CD44 variants generated through alternative splicing are involved in the development of breast cancer, but their exact role in BCSCs remains unclear. Therefore, we analyzed the CD44 transcript variants in BCSCs derived from the MDA-MB-435 cell line, and aimed to investigate whether CD44s knockdown could affect the biological characteristics of BCSCs.Methods: CD44+/CD24- cells were isolated among the MDA-MB-435 cells by flow cytometry, and the CD44 transcript variants were detected by RT-PCR in CD44+/CD24- cells. Due to the high expression of CD44 standard splice isoform (CD44s) in CD44+/CD24- cells, CD44s knockdown was generated using small hairpin RNA (shRNA). The effects of CD44s knockdown on the biological characteristics of BCSCs was detected using cell proliferation assay, colony formation assay, cell cycle and apoptosis assay, tumor sphere formation assay, would-healing assay, and Matrigel invasion assay. Tumorigenesis of the CD44+/CD24- cells with CD44s knockdown was investigated in vivo with NOD/SCID mice. The expression of cancer stem cell stemness-related genes, such as Bcl-2, CCNE2, EGFR, MMP7, Muc1, and Myc was also detected by qPCR.Results: Our results revealed that the mRNA expression of CD44 transcript variants was heterogeneous, and CD44s is highly expressed in BCSCs. CD44s depletion inhibited the proliferation, made cell cycle stay in G0/G1 phase, promoted the apoptosis and necrosis of BCSCs, inhibited the ability of self-renewal and invasion along with the expression of cancer stem cell-related genes in BCSCs. Moreover, CD44s knockdown inhibited the tumorigenesis ability in vivo.Conclusion: Our findings revealed that CD44s is the predominant isoform expressed in BCSCs, and is an important molecule for maintaining the properties of BCSCs. Targeting CD44s in BCSCs may be a potential new direction for breast cancer treatment.

Therapeutic resistance and tumor-initiation: Molecular pathways involved in breast cancer stem cell self-renewal

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 528-528 ◽  
Author(s):  
J. C. Chang ◽  
X. Li ◽  
H. Wong ◽  
C. Creighton ◽  
S. G. Hilsenbeck ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Cancer Stem Cell ◽  
Residual Disease ◽  
Molecular Pathways ◽  
Stem Cell Markers ◽  
Tumor Initiation ◽  
Self Renewal

528 Background: Recent evidence supports the existance of a rare subpopulation of ‘cancer stem cells‘ (CSCs) which is chemoresistant and capable of self-renewal and tumor-initiation, resulting in relapse and metastases. We hypothesized that residual breast tumors after conventional chemotherapy (CTx) are enriched for CSCs bearing CD44+/CD24- markers, and show increased self-renewal as demonstrated by mammosphere (MS) forming assays. Molecular pathways like Notch, Wnt, and the polycomb family that regulate normal mammary self-renewal may be in aberrant in CSCs. Methods: Paired breast cancer biopsies from 35 patients were obtained before and after 12 weeks of neoadjuvant CTx (docetaxel 100 mg/m2 or Adriamycin/Cytoxan 60/600 mg/m2, 4 cycles, q3weeks), digested by collagenase, stained with CD24/CD44/lineage antibodies, and analyzed by flow cytometry. MS assays were performed to measure self-renewal ability. Gene expression, using the Affymetrix U133 GeneChip platform, of cancer cells bearing CD44+/CD24- markers vs. all other sorted cells, and between secondary cancer MS vs. the primary bulk invasive cancers were analyzed. Results: CD44+/CD24- cells increased from a median of 4.8% to 14.8% after CTx (p<0.005). Increased self-renewal was demonstrated by an increase in MS capacity after CTx (p=0.03), with a positive correlation between the number of CD44+/24- cells and MS assays (R=0.8, p<0.05). Common molecular pathways shared by CD44+/CD24- cells and MS show increased expression in normal self-renewal pathways - polycomb family (PCGF5), Notch (MAML2), FOXP1, and BBX. In addition, genes governing alternative splicing were increased, including a non-coding RNA (MALAT1) of unknown function, and RNA splicing factors (SFRS3, SFRS21P, SFRS4). Conclusions: Our results with an increase in cells bearing stem cell markers, and increased MS formation of residual tumors provide the first strong clinical evidence for the existance of therapy-resistant cancer stem cells. Post-transcriptional regulation may play a crucial role in modifying gene function involved in cancer stem cell self-renewal. Clinical trials targeting these newly identified pathways may eradicate residual disease and improved cure rates for many breast cancer patients. [Table: see text]

scholarly journals Lipid Droplets Define a Sub-Population of Breast Cancer Stem Cells

2019 ◽  
Vol 9 (1) ◽  
pp. 87 ◽  
Author(s):  
Benjamin J. Hershey ◽  
Roberta Vazzana ◽  
Débora L. Joppi ◽  
Kristina M. Havas
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Stem Cell ◽  
Lipid Metabolism ◽  
Cancer Stem Cells ◽  
Cancer Stem Cell ◽  
Cell Lines ◽  
Lipid Droplet ◽  
Lipid Droplets ◽  
Breast Cancer Stem Cells

Tumor recurrence is now the leading cause of breast cancer-related death. These recurrences are believed to arise from residual cancer stem cells that survive initial therapeutic intervention. Therefore, a comprehensive understanding of cancer stem cell biology is needed to generate more effective therapies. Here we investigate the association between dysregulation of lipid metabolism and breast cancer stem cells. Focusing specifically on lipid droplets, we found that the lipid droplet number correlates with stemness in a panel of breast cell lines. Using a flow cytometry-based method developed for this study, we establish a means to isolate cells with augmented lipid droplet loads from total populations and show that they are enriched in cancer stem cells. Furthermore, pharmacological targeting of fatty acid metabolism reveals a metabolic addiction in a subset of cell lines. Our results highlight a key role for the lipid metabolism in the maintenance of the breast cancer stem cell pool, and as such, suggest it as a potential therapeutic target.

Biophysical analysis of cancer stem cell-potent copper(ii) coordination complexes

2019 ◽  
Vol 48 (18) ◽  
pp. 5892-5896 ◽  
Author(s):  
Puyi Zheng ◽  
Arvin Eskandari ◽  
Chunxin Lu ◽  
Kristine Laws ◽  
Leigh Aldous ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Cancer Stem Cell ◽  
Breast Cancer Cells ◽  
Coordination Complexes ◽  
Breast Cancer Stem Cells ◽  
Biophysical Analysis ◽  
Inflammatory Drugs

Copper(ii) coordination complexes, 1 and 2, containing nonsteroidal anti-inflammatory drugs (NSAIDs) potently kill breast cancer stem cells (CSCs) and bulk breast cancer cells.

scholarly journals The Role of Serotonin in Breast Cancer Stem Cells

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3171
Author(s):  
William D. Gwynne ◽  
Mirza S. Shakeel ◽  
Adele Girgis-Gabardo ◽  
John A. Hassell
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Cancer Stem Cell ◽  
Tumor Cell ◽  
Breast Tumors ◽  
Breast Cancer Stem Cells ◽  
Selective Antagonists

Breast tumors were the first tumors of epithelial origin shown to follow the cancer stem cell model. The model proposes that cancer stem cells are uniquely endowed with tumorigenic capacity and that their aberrant differentiation yields non-tumorigenic progeny, which constitute the bulk of the tumor cell population. Breast cancer stem cells resist therapies and seed metastases; thus, they account for breast cancer recurrence. Hence, targeting these cells is essential to achieve durable breast cancer remissions. We identified compounds including selective antagonists of multiple serotonergic system pathway components required for serotonin biosynthesis, transport, activity via multiple 5-HT receptors (5-HTRs), and catabolism that reduce the viability of breast cancer stem cells of both mouse and human origin using multiple orthologous assays. The molecular targets of the selective antagonists are expressed in breast tumors and breast cancer cell lines, which also produce serotonin, implying that it plays a required functional role in these cells. The selective antagonists act synergistically with chemotherapy to shrink mouse mammary tumors and human breast tumor xenografts primarily by inducing programmed tumor cell death. We hypothesize those serotonergic proteins of diverse activity function by common signaling pathways to maintain cancer stem cell viability. Here, we summarize our recent findings and the relevant literature regarding the role of serotonin in breast cancer.

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