scholarly journals Constitutive activation of MEK5 promotes a mesenchymal and migratory cell phenotype in triple negative breast cancer

Oncoscience ◽  
2021 ◽  
pp. 61
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cell Phenotype ◽  
Constitutive Activation ◽  
Migratory Cell

scholarly journals Activated STAT3 Is a Novel Regulator of the XRCC1 Promoter and Selectively Increases XRCC1 Protein Levels in Triple Negative Breast Cancer

2021 ◽  
Vol 22 (11) ◽  
pp. 5475
Author(s):  
Griffin Wright ◽  
Manoj Sonavane ◽  
Natalie R. Gassman
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Excision Repair ◽  
Strand Break ◽  
Xrcc1 Gene ◽  
Single Strand Break ◽  
Expression Levels ◽  
Constitutive Activation ◽  
Gene And Protein Expression

Base Excision Repair (BER) addresses base lesions and abasic sites induced by exogenous and endogenous stressors. X-ray cross complementing group 1 (XRCC1) functions as a scaffold protein in BER and single-strand break repair (SSBR), facilitating and coordinating repair through its interaction with a host of critical repair proteins. Alterations of XRCC1 protein and gene expression levels are observed in many cancers, including colorectal, ovarian, and breast cancer. While increases in the expression level of XRCC1 are reported, the transcription factors responsible for this up-regulation are not known. In this study, we identify the signal transducer and activator of transcription 3 (STAT3) as a novel regulator of XRCC1 through chromatin immunoprecipitation. Activation of STAT3 through phosphorylation at Y705 by cytokine (IL-6) signaling increases the expression of XRCC1 and the occupancy of STAT3 within the XRCC1 promoter. In triple negative breast cancer, the constitutive activation of STAT3 upregulates XRCC1 gene and protein expression levels. Increased expression of XRCC1 is associated with aggressiveness and resistance to DNA damaging chemotherapeutics. Thus, we propose that activated STAT3 regulates XRCC1 under stress and growth conditions, but constitutive activation in cancers results in dysregulation of XRCC1 and subsequently BER and SSBR.

scholarly journals Retinoic Acid Sensitivity of Triple-Negative Breast-Cancer Cells Characterized by Constitutive Activation of the NOTCH1 Pathway: The Role of RARβ

2020 ◽  
Author(s):  
Gabriela Paroni ◽  
Adriana Zanetti ◽  
Maria Monica Barzago ◽  
Mami Kurosaki ◽  
Luca Guarrera ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Retinoic Acid ◽  
Rna Sequencing ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Proliferative Activity ◽  
Triple Negative ◽  
Proliferation Index ◽  
Constitutive Activation ◽  
Sequencing Studies

Abstract Background: All-trans retinoic-acid (ATRA) is a promising agent in the personalized treatment/chemo-prevention of breast-cancer. Triple-negative breast-cancer (TNBC) accounts for 15-20% of all mammary tumours and share common features such as a high proliferation index and a basal-like gene expression signature. In spite of this, TNBC is very heterogeneous and lacks effective therapeutic strategies.Methods: We profile eighteen TNBC breast-cancer cell-lines for their sensitivity to the anti-proliferative action of ATRA. In addition, we perform RNA-sequencing studies in two of the most sensitive cell-lines exposed to ATRA, a γ-secretase inhibitor and combinations thereof. Results: The only three TNBC cell-lines (HCC-1599, MB-157 and MDA-MB-157) endowed with ATRA-sensitivity are characterized by constitutive activation of the NOTCH1 γ-secretase product, N1ICD and we identify the associated genetic aberrations of the NOTCH1-gene. N1ICD expression renders HCC-1599, MB-157 and MDA-MB-157 cells sensitive not only to ATRA, but also to γ-secretase inhibitors, like DAPT [N-(N-(3,5-difluorophenacetyl)-L-alanyl)-S-phenylglycine-t-butyl-ester] and PF-03084014. The anti-proliferative action of ATRA and γ-secretase inhibitors is complementary, as combinations of ATRA and DAPT or PF-03084014 cause synergistic effects. This synergism is confirmed in mouse xenografts of HCC-1599 cells. RNA-sequencing studies performed in HCC-1599 and MB-157 cells exposed to ATRA and DAPT demonstrate that the two compounds act on common gene-sets, some of which belong to the NOTCH1 pathway. ATRA inhibits the growth of HCC-1599, MB-157 and MDA-MB-157 cells via RARα, which up-regulates several retinoid target-genes, including RARβ. RARβ induction is observed only in HCC-1599, MB-157 and MDA-MB-157 cells, as the other TNBC cell-lines lack ATRA-dependent stimulation of the retinoid-receptor. RARβ is a key determinant of ATRA anti-proliferative activity, as its silencing suppresses the effects exerted by the retinoid. Conclusions: We demonstrate that ATRA exerts a significant anti-tumor action in TNBC cells characterized by constitutive NOTCH1 activation. We show that ATRA enhances the anti-tumor activity of γ-secretase inhibitors in an additive/synergistic manner. We support the idea that ATRA anti-proliferative activity is mediated by the Retinoid-Acid-Receptor-β (RARβ). The present study represents the basis for the design of clinical trials on the efficacy of combinations between ATRA and γ-secretase inhibitors in the treatment of patients affected by a specific subtype of TNBC.

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 c-Jun N-terminal kinase promotes stem cell phenotype in triple-negative breast cancer through upregulation of Notch1 via activation of c-Jun

Oncogene ◽  
2016 ◽  
Vol 36 (18) ◽  
pp. 2599-2608 ◽  
Author(s):  
X Xie ◽  
T S Kaoud ◽  
R Edupuganti ◽  
T Zhang ◽  
T Kogawa ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cell Phenotype ◽  
Stem Cell Phenotype

scholarly journals YB1 Is a Major Contributor to Health Disparities in Triple Negative Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6262
Author(s):  
Priyanka Shailendra Rana ◽  
Wei Wang ◽  
Akram Alkrekshi ◽  
Vesna Markovic ◽  
Amer Khiyami ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Black Women ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Genetic Manipulation ◽  
Healthcare Access ◽  
Cell Phenotype ◽  
Caucasian American ◽  
Racial Ethnic

Triple negative breast cancer (TNBC) is the most aggressive amongst all breast cancer (BC) subtypes. While TNBC tumors represent less than 20% of all BC subtypes, they are responsible for the most BC-related deaths. More significantly, when considering TNBC incidence across all racial/ethnic groups, TNBC accounts for less than 20% of all BCs. However, in non-Hispanic black women, the incidence rate of TNBC is more than 40%, which may be a contributing factor to the higher BC-related death rate in this population. These disparities remain strong even after accounting for differences in socioeconomic status, healthcare access, and lifestyle factors. Increased evidence now points to biological mechanisms that are intrinsic to the tumor that contribute to disparate TNBC disease burdens. Here, we show that YB1, a multifunction gene, plays a major role in the TNBC disparities between African American (AA) and Caucasian American (CA) women. We show in three independent TNBC tumors cohorts, that YB1 is significantly highly expressed in AA TNBC tumors when compared to CAs, and that increased levels of YB1 correlate with poor survival of AA patients with TNBC. We used a combination of genetic manipulation of YB1 and chemotherapy treatment, both in vitro and in animal models of TNBC to show that YB1 oncogenic activity is more enhanced in TNBC cell lines of AA origin, by increasing their tumorigenic and aggressive behaviors, trough the activation of cancer stem cell phenotype and resistance to chemotherapeutic treatments.

scholarly journals Retinoic Acid Sensitivity of Triple-Negative Breast Cancer Cells Characterized by Constitutive Activation of the notch1 Pathway: The Role of Rarβ

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3027
Author(s):  
Gabriela Paroni ◽  
Adriana Zanetti ◽  
Maria Monica Barzago ◽  
Mami Kurosaki ◽  
Luca Guarrera ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Retinoic Acid ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Target Genes ◽  
Triple Negative ◽  
Synergistic Effects ◽  
Acid Sensitivity ◽  
Constitutive Activation

Triple-negative breast cancer (TNBC) is a heterogeneous disease that lacks effective therapeutic options. In this study, we profile eighteen TNBC cell lines for their sensitivity to the anti-proliferative action of all-trans retinoic acid (ATRA). The only three cell lines (HCC-1599, MB-157 and MDA-MB-157) endowed with ATRA-sensitivity are characterized by genetic aberrations of the NOTCH1-gene, causing constitutive activation of the NOTCH1 γ-secretase product, N1ICD. N1ICD renders HCC-1599, MB-157 and MDA-MB-157 cells sensitive not only to ATRA, but also to γ-secretase inhibitors (DAPT; PF-03084014). Combinations of ATRA and γ-secretase inhibitors produce additive/synergistic effects in vitro and in vivo. RNA-sequencing studies of HCC-1599 and MB-157 cells exposed to ATRA and DAPT and ATRA+DAPT demonstrate that the two compounds act on common gene sets, some of which belong to the NOTCH1 pathway. ATRA inhibits the growth of HCC-1599, MB-157 and MDA-MB-157 cells via RARα, which up-regulates several retinoid target-genes, including RARβ. RARβ is a key determinant of ATRA anti-proliferative activity, as its silencing suppresses the effects exerted by the retinoid. In conclusion, we demonstrate that ATRA exerts a significant anti-tumor action only in TNBC cells showing constitutive NOTCH1 activation. Our results support the design of clinical trials involving combinations between ATRA and γ-secretase inhibitors for the treatment of this TNBC subtype.

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