Molecular Mechanisms Associated with Brain Metastases in HER2-Positive and Triple Negative Breast Cancers

Abstract

Breast cancer (BC) is the most frequent cause of cancer-associated death for women worldwide, with deaths commonly resulting from metastatic spread to distant organs. Approximately 30% of metastatic BC patients develop brain metastases (BM), a currently incurable diagnosis. The influence of BC molecular subtype and gene expression on breast cancer brain metastasis (BCBM) development and patient prognosis is undeniable and is, therefore, an important focus point in the attempt to combat the disease. The HER2-positive and triple-negative molecular subtypes are associated with an increased risk of developing BCBM. Several genetic and molecular mechanisms linked to HER2-positive and triple-negative BC breast cancers appear to influence BCBM formation on several levels, including increased development of circulating tumor cells (CTCs), enhanced epithelial-mesenchymal transition (EMT), and migration of primary BC cells to the brain and/or through superior local invasiveness aided by cancer stem-like cells (CSCs). These specific BC characteristics, together with the ensuing developments at a clinical level, are presented in this review article, drawing a connection between research findings and related therapeutic strategies aimed at preventing BCBM formation and/or progression. Furthermore, we briefly address the critical limitations in our current understanding of this complex topic, highlighting potential focal points for future research.

Circulating Tumor Cells in Breast Cancer Patients: A Balancing Act between Stemness, EMT Features and DNA Damage Responses

“…It starts the process by inducing the expression of a mesenchymal phenotype and eventually leads to progression and dissemination [ 20 , 62 , 73 ]. The HER2 / ERBB2 / NEU gene, amplified in 15–35% of BC cancers [ 74 , 75 ], encodes a RTK that activates EMT [ 76 ] as well as the repair of radiation-induced DNA damage [ 77 ]. Another RTK, AXL, was reported to activate EMT and HR even in TNBC cell lines [ 78 ].…”

The Role of Breast Cancer Stem Cells in Chemoresistance and Metastasis in Triple-Negative Breast Cancer

“…It has been shown that TNBC exhibits more traits possessed by CSC than other breast cancer subtypes and is more likely to develop metastases [ 57 , 58 ]. Driven by the aggregation of CD44+ CSC, more CTC clusters and polyclonal metastasis of TNBC were found to be associated with an unfavorable prognosis [ 59 ].…”

“…Driven by the aggregation of CD44+ CSC, more CTC clusters and polyclonal metastasis of TNBC were found to be associated with an unfavorable prognosis [ 59 ]. The epidermal growth factor receptor (EGFR) family has been found to be involved in the regulation of cancer metastasis, including TNBC [ 57 , 60 ]. Interactions between the receptor tyrosine kinases EGFR and metastasis with extracellular matrix (ECM)-binding integrins enhance metastatic colonization in model systems [ 60 , 61 , 62 ].…”

Insights into the Steps of Breast Cancer–Brain Metastases Development: Tumor Cell Interactions with the Blood–Brain Barrier

“…Depending on the expression or lack of certain receptors, tumors can be classified into one of the following three main groups: estrogen/progesterone-receptor-positive (ER+/PR+), human epidermal growth factor receptor 2 positive (HER2+), and triple-negative (TNBC), the latter showing the worst survival rate and, therefore, representing the most aggressive form [14]. Concerning the development of BM, previous studies have shown that patients of the TNBC and HER2+ subtype have a higher risk of developing BM, and several factors associated with BM in HER2-positive and TNBC have been identified [16][17][18][19]. BM development is a complex and multistage process.…”