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

Abstract

Identification of brain metastasis genes and therapeutic evaluation of histonewas not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/296384 doi: bioRxiv preprint first posted online Apr. 6, 2018; was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/296384 doi: bioRxiv preprint first posted online Apr. 6, 2018; 3 SUMMARY STATEMENT 47We introduce a new syngeneic mouse model of spontaneous breast cancer brain metastasis, 48 demonstrate its phenotypic, functional and transcriptomic relevance to human TNBC brain 49 metastasis and test novel therapies. 50 51 All rights reserved. No reuse allowed without permission.was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/296384 doi: bioRxiv preprint first posted online Apr. 6, 2018; 4 ABSTRACT 52 Breast cancer brain metastasis remains largely incurable. While several mouse models have 53 been developed to investigate the genes and mechanisms regulating breast cancer brain 54 metastasis, these models often lack clinical relevance since they require the use of immune-55 compromised mice and/or are poorly metastatic to brain from the mammary gland. We 56 describe the development and characterisation of an aggressive brain metastatic variant of the 57 4T1 syngeneic model (4T1Br4) that spontaneously metastasises to multiple organs, but is 58 selectively more metastatic to the brain from the mammary gland than parental 4T1 tumours. 59By immunohistochemistry, 4T1Br4 tumours and brain metastases display a triple negative 60 phenotype, consistent with the high propensity of this breast cancer subtype to spread to brain. 61In vitro assays indicate that 4T1Br4 cells have an enhanced ability to adhere to or migrate 62 across a brain-derived endothelial monolayer and greater invasive response to brain- was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/296384 doi: bioRxiv preprint first posted online Apr. 6, 2018; 5 INTRODUCTION 74Metastasis accounts for the majority of breast cancer-related mortalities and approximately 75 40,000 women were expected to die from the disease in 2017 in the US alone (Ghoncheh et 76 al., 2016). The incidence of brain metastasis in breast cancer patients is estimated at ~30% 77 and is rising, despite more effective systemic therapies (Tabouret et al., 2012). Therapeutic 78 options consist primarily of surgery, whole brain radiation therapy, stereotactic radiosurgery 79 and chemotherapy but these approaches, while extending life, are rarely curative (Eichler et 80 al., 2011). While surgical rese...

Neoadjuvant neratinib promotes ferroptosis and inhibits brain metastasis in a novel syngeneic model of spontaneous HER2+ve breast cancer metastasis

“…The 67NR (provided by Dr. F. Miller, Karmanos Cancer Institute, Detroit, MI, USA), the 4T1.2 and the brainmetastatic 4T1Br4 mouse mammary carcinoma cell lines were derived from a BALB/C spontaneous mammary tumour and cultured as described previously [34,35]. Primary translational breast cancer program-1 (TBCP-1) cells were isolated from a spontaneously arising mammary tumour in a BALB/C mouse (SMT1 kindly donated by Dr. Judy Harmey, Royal College of Surgeons in Ireland) and adapted to culture, from nutrient-rich medium [Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% foetal bovine serum (FBS), epidermal growth factor (EGF, 10 ng/ml), insulin (5 μg/ml), glutamine (2 mM), sodium pyruvate (1 mM) and 1% penicillin/ streptomycin] to low nutrient medium [DMEM, 10% FBS, sodium pyruvate (1 mM), 1% penicillin/streptomycin] over several months (Additional file 1: Figure S1A).…”

“…Cell proliferation was measured using a sulforhodamine B (SRB) colorimetric assay as described previously with minor modifications [34,37]. Briefly, TBCP-1 (1 × 10 3 ) or SKBR3 (2 × 10 3 ) cells were seeded in triplicate wells of a 96-well plate in 100 μl of serum-containing medium and allowed to adhere at 37°C for 6 h. Inhibitors were added in 100 μl of the same medium and proliferation measured over 5 days.…”

Bifunctional Aptamer–Doxorubicin Conjugate Crosses the Blood–Brain Barrier and Selectively Delivers Its Payload to EpCAM-Positive Tumor Cells

“…MDA-MB-231Br cells (10 5 cells/100 mL 0.9% saline solution) were inoculated directly into the left cardiac ventricle of 6-to 8-week-old NOD SCID gamma (NSG) female mice, as described previously [27,28]. Mice were monitored daily TARGETING BREAST CANCER BRAIN METASTASES after cell injection for signs of ill health due to metastasis.…”

Marizomib suppresses triple-negative breast cancer via proteasome and oxidative phosphorylation inhibition

“…To overcome the potential confounding effects on primary tumor growth, we next investigated the effect of Mzb on spontaneous or established lung and brain metastasis using a more aggressive syngeneic murine 4T1BR4 TNBC model. The 4T1BR4 cells are derived from the parental 4T1 cells with approximately 20% uptake rate in the brain and 60% uptake rate in the lungs (23). Following the engraftment of 4T1BR4 cell and once the tumor size reached ~250-300 mm 3 , we surgically resected the primary tumors.…”