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Building Up a High-throughput Screening Platform to Assess the Heterogeneity of HER2 Gene Amplification in Breast Cancers
Published on: December 5, 2017
HER2 in stemness and epithelial-mesenchymal plasticity of breast cancer
1Algoma District Cancer Program, Sault Area Hospital, 750 Great Northern Road, Sault Ste. Marie, ON, P6B 0A8, Canada. ivoutsadakis@yahoo.com.
Abstract:
Breast cancer had been the first non-hematologic malignancy where sub-types based on molecular characterization had entered clinical practice. HER2 over-expression, due to either gene amplification or protein up-regulation, defines one of these sub-types and is clinically exploited by addition of HER2-targeted treatments to the regimens of treatment. Nevertheless, in many occasions HER2-positive cancers are resistant or become refractory to these therapies. Several mechanisms, such as activation of alternative pathways or loss of expression of the receptor in cancer cells, have been proposed as the cause of these therapeutic failures. Cancer stem cells (CSCs, alternatively called tumor-initiating cells) comprise a small percentage of the tumor cells, but are capable of reconstituting and propagating tumors due to their superior intrinsic capacity for regeneration, survival and resistance to therapies. CSCs possess circuits enabling epigenetic plasticity which endow them with the ability to alternate between epithelial and mesenchymal states. This paper will discuss the expression and regulation of HER2 in CSCs of the different sub-types of breast cancer and relationships of the receptor with both the circuits of stemness and epithelial-mesenchymal plasticity. Therapeutic repercussions of the relationship of HER2-initiated signaling with stemness networks will also be proposed.
Insights
HER2-positive breast cancers can resist HER2-targeted therapies. Cancer stem cells (CSCs) play a role in this resistance by regulating HER2 expression and plasticity, impacting treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Breast cancer subtyping relies on molecular characteristics, with HER2 over-expression identifying a targetable subtype.
- HER2-targeted therapies are standard for HER2-positive breast cancer but often face resistance or refractoriness.
- Mechanisms of resistance include alternative pathway activation and loss of HER2 receptor expression.
Purpose of the Study:
- To discuss the expression and regulation of HER2 in breast cancer stem cells (CSCs).
- To explore the relationship between HER2, stemness circuits, and epithelial-mesenchymal plasticity in CSCs.
- To propose therapeutic implications of HER2 signaling in CSCs.
Main Methods:
- Review of existing literature on HER2 expression in breast cancer stem cells.
- Analysis of proposed mechanisms for HER2 regulation and its link to stemness and plasticity.
- Discussion of therapeutic strategies targeting HER2-stemness interactions.
Main Results:
- HER2 expression and regulation in CSCs are complex and vary across breast cancer subtypes.
- CSCs exhibit epigenetic plasticity, enabling transitions between epithelial and mesenchymal states, influencing HER2.
- HER2 signaling pathways are intertwined with stemness networks, contributing to therapeutic resistance.
Conclusions:
- Understanding HER2 dynamics in CSCs is crucial for overcoming treatment resistance in HER2-positive breast cancer.
- Targeting the interplay between HER2, stemness, and plasticity may offer novel therapeutic avenues.
- Further research into CSC-specific HER2 regulation is needed to improve patient outcomes.
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