Abstract
Blood-borne metastasis to the brain is a major complication of breast cancer, but cellular pathways that enable cancer cells to selectively grow in the brain microenvironment are poorly understood. We find that cultured circulating tumor cells (CTCs), derived from blood samples of women with advanced breast cancer and directly inoculated into the mouse frontal lobe, exhibit striking differences in proliferative potential in the brain. Derivative cell lines generated by serial intracranial injections acquire selectively increased proliferative competency in the brain, with reduced orthotopic tumor growth. Increased Hypoxia Inducible Factor 1A (HIF1A)-associated signaling correlates with enhanced proliferation in the brain, and shRNA-mediated suppression of HIF1A or drug inhibition of HIF-associated glycolytic pathways selectively impairs brain tumor growth while minimally impacting mammary tumor growth. In clinical specimens, brain metastases have elevated HIF1A protein expression, compared with matched primary breast tumors, and in patients with brain metastases, hypoxic signaling within CTCs predicts decreased overall survival. The selective activation of hypoxic signaling by metastatic breast cancer in the brain may have therapeutic implications.
Highlights
Blood-borne metastasis to the brain is a major complication of breast cancer, but cellular pathways that enable cancer cells to selectively grow in the brain microenvironment are poorly understood
To directly test the proliferative properties of breast cancer-derived circulating tumor cells (CTCs) in the brain, we established a model for stereotactic injection of GFP- and luciferasetagged cells into the right frontal lobe of immunosuppressed NSG mice
Moderate growth was demonstrated by two other CTC lines (Brx-50, Brx-82), one of which was derived from a patient with multiple intracranial metastases (Brx-82)
Summary
Blood-borne metastasis to the brain is a major complication of breast cancer, but cellular pathways that enable cancer cells to selectively grow in the brain microenvironment are poorly understood. Increased Hypoxia Inducible Factor 1A (HIF1A)-associated signaling correlates with enhanced proliferation in the brain, and shRNA-mediated suppression of HIF1A or drug inhibition of HIF-associated glycolytic pathways selectively impairs brain tumor growth while minimally impacting mammary tumor growth. We used serial tumor enrichment of breast CTC lines to generate derivatives with proficiency for proliferation in the brain, and we identify hypoxia and HIF1A pathways as selectively upregulated. We corroborate these findings in clinical brain metastasis samples, in which we observe increased HIF1A and hypoxic signaling versus matched primary breast tumor samples. Suppression of HIF1A signaling in breast CTCs abrogates their tumorigenesis in the brain without affecting orthotopic proliferation in the mammary gland, revealing a differential requirement for hypoxic signaling in the brain environment
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