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.

Breast cancer (BC) is the most common tumour in women. Although the introduction of novel therapeutic approaches in clinical practice has dramatically improved the clinical outcome of BC patients, this malignant disease remains the second leading cause of cancer-related death worldwide. The wingless/integrated (Wnt) signalling pathway represents a crucial molecular node relevantly implicated in the regulation of normal somatic stem cells as well as cancer stem cell (CSC) traits and the epithelial–mesenchymal transition cell program. Accordingly, Wnt signalling is heavily dysregulated in BC, and the altered expression of different Wnt genes is significantly associated with cancer-related aggressive behaviours. For all these reasons, Wnt signalling represents a promising therapeutic target currently under clinical investigation to achieve cancer eradication by eliminating CSCs, considered by most to be responsible for tumour initiation, relapse, and drug resistance. In this review, we summarized the current knowledge on the Wnt signalling pathway in BC and have presented evidence implicating the suitability of Wnt targeting in an attempt to improve the outcome of patients without affecting the normal somatic stem cell population.

Although the introduction of immunotherapy has tremendously improved the prognosis of patients with metastatic cancers of different histological origins, some tumors fail to respond or develop resistance. Broadening the clinical efficacy of currently available immunotherapy strategies requires an improved understanding of the biological mechanisms underlying cancer immune escape. Globally, tumor cells evade immune attack using two main strategies: avoiding recognition by immune cells and instigating an immunosuppressive tumor microenvironment. Emerging data suggest that the clinical efficacy of chemotherapy or molecularly targeted therapy is related to the ability of these therapies to target cancer stem cells (CSCs). However, little is known about the role of CSCs in mediating tumor resistance to immunotherapy. Due to their immunomodulating features and plasticity, CSCs can be especially proficient at evading immune surveillance, thus potentially representing the most prominent malignant cell component implicated in primary or acquired resistance to immunotherapy. The identification of immunomodulatory properties of CSCs that include mechanisms that regulate their interactions with immune cells, such as bidirectional release of particular cytokines/chemokines, fusion of CSCs with fusogenic stromal cells, and cell-to-cell communication exerted by extracellular vesicles, may significantly improve the efficacy of current immunotherapy strategies. The purpose of this review is to discuss the current scientific evidence linking CSC biological, immunological, and epigenetic features to tumor resistance to immunotherapy.

Human epidermal growth factor receptor 2 (ERBB2 or HER2) amplification/overexpression is associated with a particularly aggressive molecular subtype of breast cancer (BC), characterized by a poor prognosis, increased metastatic potential, and disease recurrence. As only approximately 50% of HER2-positive patients respond to HER2-targeted therapies, greater knowledge of the biology of HER2 and the mechanisms that underlie drug susceptibility is needed to improve cure rates. Evidence suggests that the coexistence of full-length, wild-type HER2 (wtHER2) and altered forms of HER2—such as carboxy-terminus-truncated fragments, activating mutations, and splice variants—significantly increases the heterogeneity of HER2-positive disease, affecting its biology, clinical course, and treatment response. In particular, expression of the d16HER2 splice variant in human HER2-positive BC has a crucial pathobiological function, wherein the absence of sixteen amino acids from the extracellular domain induces the formation of stable and constitutively active HER2 homodimers on the tumor cell surface. Notably, the d16HER2 variant significantly influences the initiation and aggressiveness of tumors, cancer stem cell properties, epithelial–mesenchymal transition (EMT), and the susceptibility of HER2-positive BC cells to trastuzumab compared with its wtHER2 counterpart, thus constituting a novel and potentially clinically useful biomarker. The aims of this review are to summarize the existing evidence regarding the pathobiological functions of the d16HER2 variant and discuss its current and future value with regard to risk assessment and treatment choices in HER2-positive disease.