Molecular and cellular mechanisms underlying brain metastasis of breast cancer

Abstract

Metastasis of cancer cells to the brain occurs frequently in patients with certain subtypes of breast cancer. In particular, patients with HER2-positive or triple-negative breast cancer are at high risk for the development of brain metastases. Despite recent advances in the treatment of primary breast tumors, the prognosis of breast cancer patients with brain metastases remains poor. A better understanding of the molecular and cellular mechanisms underlying brain metastasis might be expected to lead to improvements in the overall survival rate for these patients. Recent studies have revealed complex interactions between metastatic cancer cells and their microenvironment in the brain. Such interactions result in the activation of various signaling pathways related to metastasis in both cancer cells and cells of the microenvironment including astrocytes and microglia. In this review, we focus on such interactions and on their role both in the metastatic process and as potential targets for therapeutic intervention.

Keywords: Astrocyte; Brain metastasis; Breast cancer; PI3K-Akt; STAT3; xCT.

Fig. 1

Models for the interactions between tumor cells and the tumor microenvironment in the brain. a The STAT3 and NF-κB signaling pathways play key roles in tumor-associated astrocytes in brain metastases. (a) Reactive astrocytes show phosphorylation of STAT3 and expression of PD-L1, which may contribute to the suppression of CD8⁺ T cell function [26]. (b) Reactive astrocytes positive for STAT3 activation increase the number of CD74⁺ microglia-macrophages in brain metastases through production of the CD74 ligand MIF and consequent activation of the MIF-CD74 axis [26]. (c) The NF-κB pathway is activated in CD74⁺ microglia-macrophages [26]. (d) Cross talk between microglia-macrophages and astrocytes contributes to establishment of an immunosuppressive environment in primary brain tumors [28]. (e) Cancer cells transfer cGAMP to astrocytes through Cx43-PCDH7 gap junctions, resulting in activation of the cGAS-STING pathway in the latter cells [32]. (f, g) Production of IFN-α and TNF-α by astrocytes induces activation of STAT1 and NF-κB pathways in cancer cells and thereby supports brain metastasis [32]. b. The PI3K-Akt signaling pathway plays a key role in brain metastases of breast cancer cells. (h) PI3K activation up-regulates PD-L1 and CTLA4 expression in cancer cells [33]. (i) Cross talk between cancer cells and macrophages results in activation of PI3K and CSF1-CSF1R signaling in macrophages [33]. (j) PI3Kγ signaling in macrophages inhibits NF-κB activation and promotes immune suppression in head and neck cancer [38]. (k) Loss of PTEN expression in cancer cells is induced epigenetically by exosomal miRNAs released from astrocytes [41]. (l, m) PTEN loss results in increased expression of the chemokine CCL2 and activation of NF-κB signaling in cancer cells as well as in the consequent CCR2-dependent recruitment of macrophages [41]