TY - JOUR
T1 - Her2 signaling and breast cancer stem cells
T2 - The bridge behind her2-positive breast cancer aggressiveness and therapy refractoriness
AU - Pupa, Serenella M.
AU - Ligorio, Francesca
AU - Cancila, Valeria
AU - Franceschini, Alma
AU - Tripodo, Claudio
AU - Vernieri, Claudio
AU - Castagnoli, Lorenzo
N1 - Funding Information:
Data generated in the Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan were funded by grants from the Associazione Italiana Ricerca Cancro (AIRC) (call 2010 Id. 10352 and call 2015 Id. 16918 to S.M. Pupa) and Ministero Italiano della Salute (RF-2009-1532281 to S.M. Pupa); this work was partially funded by the AIRC (under IG 2019?ID. 22943 project?P.I.S.M. Pupa). L. Castagnoli was the recipient of a fellowship from the AIRC (call 2014 Id 15002) and a fellowship from the Fondazione Pezcoller (call 2020).
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/10/1
Y1 - 2021/10/1
N2 - HER2 overexpression/amplification occurs in 15–20% of breast cancers (BCs) and identifies a highly aggressive BC subtype. Recent clinical progress has increased the cure rates of limited-stage HER2-positive BC and significantly prolonged overall survival in patients with advanced disease; however, drug resistance and tumor recurrence remain major concerns. Therefore, there is an urgent need to increase knowledge regarding HER2 biology and implement available treatments. Cancer stem cells (CSCs) represent a subset of malignant cells capable of unlimited self-renewal and differentiation and are mainly considered to contribute to tumor onset, aggressiveness, metastasis, and treatment resistance. Seminal studies have highlighted the key role of altered HER2 signaling in the maintenance/enrichment of breast CSCs (BCSCs) and elucidated its bidirectional communication with stemness-related pathways, such as the Notch and Wingless/β-catenin cascades. d16HER2, a splice variant of full-length HER2 mRNA, has been identified as one of the most oncogenic HER2 isoform significantly implicated in tumorigenesis, epithelial-mesenchymal transition (EMT)/stemness and the response to targeted therapy. In addition, expression of a heterogeneous collection of HER2 truncated carboxy-terminal fragments (CTFs), collectively known as p95HER2, identifies a peculiar subgroup of HER2-positive BC with poor prognosis, with the p95HER2 variants being able to regulate CSC features. This review provides a comprehensive overview of the current evidence regarding HER2-/d16HER2-/p95HER2-positive BCSCs in the context of the signaling pathways governing their properties and describes the future prospects for targeting these components to achieve long-lasting tumor control.
AB - HER2 overexpression/amplification occurs in 15–20% of breast cancers (BCs) and identifies a highly aggressive BC subtype. Recent clinical progress has increased the cure rates of limited-stage HER2-positive BC and significantly prolonged overall survival in patients with advanced disease; however, drug resistance and tumor recurrence remain major concerns. Therefore, there is an urgent need to increase knowledge regarding HER2 biology and implement available treatments. Cancer stem cells (CSCs) represent a subset of malignant cells capable of unlimited self-renewal and differentiation and are mainly considered to contribute to tumor onset, aggressiveness, metastasis, and treatment resistance. Seminal studies have highlighted the key role of altered HER2 signaling in the maintenance/enrichment of breast CSCs (BCSCs) and elucidated its bidirectional communication with stemness-related pathways, such as the Notch and Wingless/β-catenin cascades. d16HER2, a splice variant of full-length HER2 mRNA, has been identified as one of the most oncogenic HER2 isoform significantly implicated in tumorigenesis, epithelial-mesenchymal transition (EMT)/stemness and the response to targeted therapy. In addition, expression of a heterogeneous collection of HER2 truncated carboxy-terminal fragments (CTFs), collectively known as p95HER2, identifies a peculiar subgroup of HER2-positive BC with poor prognosis, with the p95HER2 variants being able to regulate CSC features. This review provides a comprehensive overview of the current evidence regarding HER2-/d16HER2-/p95HER2-positive BCSCs in the context of the signaling pathways governing their properties and describes the future prospects for targeting these components to achieve long-lasting tumor control.
KW - Breast cancer
KW - Cancer stem cells
KW - D16HER2 splice variant
KW - Drug resistance
KW - Full-length HER2
KW - P95HER2
KW - Stemness signaling pathways
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U2 - 10.3390/cancers13194778
DO - 10.3390/cancers13194778
M3 - Review article
AN - SCOPUS:85115651613
SN - 2072-6694
VL - 13
JO - Cancers
JF - Cancers
IS - 19
M1 - 4778
ER -