Identification of brain metastasis genes and therapeutic evaluation of histone deacetylase inhibitors in a clinically relevant model of breast cancer brain metastasis

Abstract

Breast cancer brain metastases remain largely incurable. Although several mouse models have been developed to investigate the genes and mechanisms regulating breast cancer brain metastasis, these models often lack clinical relevance since they require the use of immunocompromised mice and/or are poorly metastatic to brain from the mammary gland. We describe the development and characterisation of an aggressive brain metastatic variant of the 4T1 syngeneic model (4T1Br4) that spontaneously metastasises to multiple organs, but is selectively more metastatic to the brain from the mammary gland than parental 4T1 tumours. As seen by immunohistochemistry, 4T1Br4 tumours and brain metastases display a triple-negative phenotype, consistent with the high propensity of this breast cancer subtype to spread to brain. In vitro assays indicate that 4T1Br4 cells have an enhanced ability to adhere to or migrate across a brain-derived endothelial monolayer and greater invasive response to brain-derived soluble factors compared to 4T1 cells. These properties are likely to contribute to the brain selectivity of 4T1Br4 tumours. Expression profiling and gene set enrichment analyses demonstrate the clinical relevance of the 4T1Br4 model at the transcriptomic level. Pathway analyses implicate tumour-intrinsic immune regulation and vascular interactions in successful brain colonisation, revealing potential therapeutic targets. Evaluation of two histone deacetylase inhibitors, SB939 and 1179.4b, shows partial efficacy against 4T1Br4 metastasis to brain and other sites in vivo, and potent radio-sensitising properties in vitro. The 4T1Br4 model provides a clinically relevant tool for mechanistic studies and to evaluate novel therapies against brain metastasis..

Blocking c-MET/ERBB1 Axis Prevents Brain Metastasis in ERBB2+ Breast Cancer

“…In this study, we reported an orthotopic model of spontaneous ERBB2 + BC BrM that can be used to evaluate therapeutic approaches targeting both the primary tumor and distant metastases together, suggesting its high clinical relevance. Previously, an orthotopic mouse model of BrM using triple-negative cell lines MDA-MB-231 and 4T1 have been reported in NSG and BALB/c mice, respectively, which are suitable for therapeutic modalities against TNBC [49][50][51][52]. In the ERBB2 + BC subtype, both intracardiac and intracarotid models have been used for the evaluation of therapeutic modalities against BC BrM [24,25,53].…”

Radiotherapy in Preclinical Models of Brain Metastases: A Review and Recommendations for Future Studies

“…Intravenous (IV) inoculation (tail vein injection) is uncommon due to the low incidence of BM formation and inevitable lung metastases. Spontaneous models frequently form a single lesion in the BM 58 , reflecting the actual process from tumor occurrence to metastasis. However, extensive use is hindered by the prolonged experimental period and metastases throughout the body 68 .…”

The origin of brain malignancies at the blood–brain barrier

“…Numerous cell-surface molecules located on the tumor cell or endothelial surface are implicated in the formation and outgrowth of brain metastases (Table 4 ). These include ALCAM [ 175 – 177 ], PECAM1 [ 178 ], L1CAM [ 179 , 180 ], melanotransferrin [ 181 ], E-Selectin [ 155 , 156 , 182 – 186 ], and E-cadherin/ N-cadherin [ 187 – 190 ].…”