HER2 Signaling and Breast Cancer Stem Cells: The Bridge behind HER2-Positive Breast Cancer Aggressiveness and Therapy Refractoriness

Abstract

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.

Blocking Gi/o-Coupled Signaling Eradicates Cancer Stem Cells and Sensitizes Breast Tumors to HER2-Targeted Therapies to Inhibit Tumor Relapse

“…Increasing evidence demonstrates that the aggressiveness, therapy-resistance, and disease-relapse exhibited by HER2+ breast cancer might be attributed to the presence of a small sub-population of cancer stem cells (CSCs) [ 6 , 7 , 8 ]. This study identifies Gi/o-GPCR signaling as a key activity driving CSC function in HER2-induced breast cancer, where HER2 overexpression by CSCs stimulates their tumorigenicity.…”

“…Cells expressing CSC markers (e.g., CD44 + /CD24 − ) and with high aldehyde dehydrogenase (ALDH) activity were identified as a subset of cells in both breast cancer cell lines and human tumor tissues that could self-renew and initiate and maintain tumor growth [ 4 , 5 ]. Notably, the aggressive human HER2+ breast cancer subtype is enriched with CSCs, suggesting they contribute to the poor clinical prognosis for HER2+ breast cancer, one prone to recurrence and metastasis [ 6 , 7 , 8 ]. Indeed, HER2 overexpression can drive CSC expansion, and the effectiveness of HER2-targeted therapy (e.g., trastuzumab) is linked to the capacity to eradicate CSCs [ 6 , 9 , 10 , 11 ].…”

Blocking Gi/o-coupled signaling eradicates cancer stem cells and sensitizes breast tumors to HER2-targeted therapies to inhibit tumor relapse

“…Increasing evidence demonstrates that the aggressiveness, therapy-resistance, and disease-relapse exhibited by HER2+ breast cancer might be attributed to the presence of a small sub-population of cancer stem cells (CSCs) (Korkaya et al ., 2008; Korkaya and Wicha, 2013; Pupa et al ., 2021). This study identifies Gi/o-GPCR signaling as a key activity driving CSC function in HER2-induced breast cancer, where HER2 overexpression by CSCs stimulates their tumorigenicity.…”

“…The presence of CSCs is thought to make HER2+ breast cancer resistant to HER2-targeted therapy, allowing tumors to re-emerge after treatment (Pupa et al ., 2021). Consistent with this idea, we found trastuzumab and lapatinib only partially inhibited CSC activity in the therapy-sensitive cell lines, BT474 and Neu, while trastuzumab had no effect on CSCs in the trastuzumab-resistant cell line, BT474R.…”

“…Cells expressing CSC markers (e.g., CD44 + /CD24 - ) and with high aldehyde dehydrogenase (ALDH) activity were identified as a subset of cells in both breast cancer cell lines and human tumor tissues that could self-renew and initiate and maintain tumor growth (Al-Hajj et al, 2003; Ginestier et al, 2007). Notably, the aggressive human HER2+ breast cancer subtype is enriched with CSCs, suggesting they contribute to the poor clinical prognosis for HER2+ breast cancer, one prone to recurrence and metastasis (Korkaya et al, 2008; Korkaya and Wicha, 2013; Pupa et al, 2021). Indeed, HER2 overexpression can drive CSC expansion, and the effectiveness of HER2-targeted therapy (e.g.,trastuzumab) is linked to the capacity to eradicate CSCs (Ithimakin et al, 2013; Korkaya et al ., 2008; Magnifico et al, 2009; Martin-Castillo et al, 2015).…”