Research advances and new challenges in overcoming triple-negative breast cancer

Zong, Yu; Pegram, Mark D.

doi:10.20517/cdr.2021.04

Cited by 17 publications

(22 citation statements)

References 142 publications

(283 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent articles have reviewed the importance of CSCs in TNBC progression and therapeutic resistance [ 18 , 19 , 20 , 21 , 22 , 23 ]. TNBCs are enriched with CD44+/CD24−/ALDH1+ CSCs that contribute to metastases, chemoresistance and poor clinical outcomes [ 24 , 25 , 26 , 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

Addiction of Cancer Stem Cells to MUC1-C in Triple-Negative Breast Cancer Progression

Yamashita

Küfe

2022

IJMS

View full text Add to dashboard Cite

Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited treatment options. TNBC progression is associated with expansion of cancer stem cells (CSCs). Few insights are available regarding druggable targets that drive the TNBC CSC state. This review summarizes the literature on TNBC CSCs and the compelling evidence that they are addicted to the MUC1-C transmembrane protein. In normal epithelia, MUC1-C is activated by loss of homeostasis and induces reversible wound-healing responses of inflammation and repair. However, in settings of chronic inflammation, MUC1-C promotes carcinogenesis. MUC1-C induces EMT, epigenetic reprogramming and chromatin remodeling in TNBC CSCs, which are dependent on MUC1-C for self-renewal and tumorigenicity. MUC1-C-induced lineage plasticity in TNBC CSCs confers DNA damage resistance and immune evasion by chronic activation of inflammatory pathways and global changes in chromatin architecture. Of therapeutic significance, an antibody generated against the MUC1-C extracellular domain has been advanced in a clinical trial of anti-MUC1-C CAR T cells and in IND-enabling studies for development as an antibody–drug conjugate (ADC). Agents targeting the MUC1-C cytoplasmic domain have also entered the clinic and are undergoing further development as candidates for advancing TNBC treatment. Eliminating TNBC CSCs will be necessary for curing this recalcitrant cancer and MUC1-C represents a promising druggable target for achieving that goal.

show abstract

Section: Introductionmentioning

confidence: 99%

Addiction of Cancer Stem Cells to MUC1-C in Triple-Negative Breast Cancer Progression

Yamashita

Küfe

2022

IJMS

View full text Add to dashboard Cite

show abstract

“…Initially, only five distinct subtypes of breast cancer were identified: Luminal A, Luminal B, HER2 enriched, basal-like, and normal breast-like. In general, tumours that neither express oestrogen receptor (ER), progesterone receptor (PR), nor human epidermal growth factor receptor 2 (HER2) are defined as triple-negative breast cancer (TNBC) [ 29 ]. TNBC subtypes are subject to poor prognosis as conventional treatments such as hormonal therapy and HER2 targeted therapy have to be ruled out due to the absence of the corresponding receptors.…”

Section: The Roles Of Nav15 and Nnav15 In Potentiating The Progressio...mentioning

confidence: 99%

Discovering the Triad between Nav1.5, Breast Cancer, and the Immune System: A Fundamental Review and Future Perspectives

et al. 2022

View full text Add to dashboard Cite

Nav1.5 is one of the nine voltage-gated sodium channel-alpha subunit (VGSC-α) family members. The Nav1.5 channel typically carries an inward sodium ion current that depolarises the membrane potential during the upstroke of the cardiac action potential. The neonatal isoform of Nav1.5, nNav1.5, is produced via VGSC-α alternative splicing. nNav1.5 is known to potentiate breast cancer metastasis. Despite their well-known biological functions, the immunological perspectives of these channels are poorly explored. The current review has attempted to summarise the triad between Nav1.5 (nNav1.5), breast cancer, and the immune system. To date, there is no such review available that encompasses these three components as most reviews focus on the molecular and pharmacological prospects of Nav1.5. This review is divided into three major subsections: (1) the review highlights the roles of Nav1.5 and nNav1.5 in potentiating the progression of breast cancer, (2) focuses on the general connection between breast cancer and the immune system, and finally (3) the review emphasises the involvements of Nav1.5 and nNav1.5 in the functionality of the immune system and the immunogenicity. Compared to the other subsections, section three is pretty unexploited; it would be interesting to study this subsection as it completes the triad.

show abstract

“…There is no reliable prognostic biomarker that can be used to predict with certainty and molecular precision which RCB (I-II-III) tumors will stay in remission and which ones will relapse rapidly [ 3 ] . Few therapeutic agents, alone or in combination, are effective at eradicating chemoresistant and metastatic TNBC [ 57 - 60 ] . Therefore, the development of a new tumor-specific biomarker that can be used to stratify high-risk TNBC patients in the first-line neoadjuvant setting, quantifying treatment efficacy in real time in the clinical setting is essential.…”

Section: Introductionmentioning

confidence: 99%

“…Chemo-resistance is a vexing problem and a major life-threatening feature of TNBC [ 25 , 57 , 61 ] . Activation of multiple signaling pathways, context-dependent compensatory pathway cross-talk, synergy, antagonism, and signaling network “rewiring” are all implicated in the development of chemoresistant phenotypes in TNBC.…”

Section: Introductionmentioning

confidence: 99%

Persistent EGFR/K-RAS/SIAH pathway activation drives chemo-resistance and early tumor relapse in triple-negative breast cancer

et al. 2022

View full text Add to dashboard Cite

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. It disproportionately affects BRCA mutation carriers and young women, especially African American (AA) women. Chemoresistant TNBC is a heterogeneous and molecularly unstable disease that challenges our ability to apply personalized therapies. With the approval of immune checkpoint blockade (ICB) for TNBC, the addition of pembrolizumab to systemic chemotherapy has become standard of care (SOC) in neoadjuvant systemic therapy (NST) for high-risk early-stage TNBC. Pembrolizumab plus chemotherapy significantly increased the pathologic complete response (pCR) and improved event-free survival in TNBC. However, clinical uncertainties remain because similarly treated TNBC partial responders with comparable tumor responses to neoadjuvant therapy often experience disparate clinical outcomes. Current methods fall short in accurately predicting which high-risk patients will develop chemo-resistance and tumor relapse. Therefore, novel treatment strategies and innovative new research initiatives are needed. We propose that the EGFR-K-RAS-SIAH pathway activation is a major tumor driver in chemoresistant TNBC. Persistent high expression of SIAH in residual tumors following NACT/NST reflects that the EGFR/K-RAS pathway remains activated (ON), indicating an ineffective response to treatment. These chemoresistant tumor clones persist in expressing SIAH (SIAHHigh/ON) and are linked to early tumor relapse and poorer prognosis. Conversely, the loss of SIAH expression (SIAHLow/OFF) in residual tumors post-NACT/NST reflects EGFR/K-RAS pathway inactivation (OFF), indicating effective therapy and chemo-sensitive tumor cells. SIAHLow/OFF signal is linked to tumor remission and better prognosis post-NACT/NST. Therefore, SIAH is well-positioned to become a novel tumor-specific, therapy-responsive, and prognostic biomarker. Potentially, this new biomarker (SIAHHigh/ON) could be used to quantify therapy response, predict chemo-resistance, and identify those patients at the highest risk for tumor relapse and poor survival in TNBC.

show abstract

Research advances and new challenges in overcoming triple-negative breast cancer

Abstract: How to cite this article: Zong Y, Pegram M. Research advances and new challenges in overcoming triple-negative breast cancer.

Cited by 17 publications

References 142 publications

Addiction of Cancer Stem Cells to MUC1-C in Triple-Negative Breast Cancer Progression

Addiction of Cancer Stem Cells to MUC1-C in Triple-Negative Breast Cancer Progression

Discovering the Triad between Nav1.5, Breast Cancer, and the Immune System: A Fundamental Review and Future Perspectives

Persistent EGFR/K-RAS/SIAH pathway activation drives chemo-resistance and early tumor relapse in triple-negative breast cancer

Contact Info

Product

Resources

About