HIF1A signaling selectively supports proliferation of breast cancer in the brain

Richard Y. Ebright, Marcus A. Zachariah, Douglas S. Micalizzi, Ben S. Wittner, Kira L. Niederhoffer, Linda T. Nieman, Brian Chirn, Devon F. Wiley, Benjamin Wesley, Brian Shaw, Edwin Nieblas-Bedolla, Lian Atlas, Annamaria Szabolcs, Anthony J. Iafrate, Mehmet Toner, David T. Ting, Priscilla K. Brastianos, Daniel A. Haber () and Shyamala Maheswaran ()
Additional contact information
Richard Y. Ebright: Harvard Medical School
Marcus A. Zachariah: Harvard Medical School
Douglas S. Micalizzi: Harvard Medical School
Ben S. Wittner: Harvard Medical School
Kira L. Niederhoffer: Harvard Medical School
Linda T. Nieman: Harvard Medical School
Brian Chirn: Harvard Medical School
Devon F. Wiley: Harvard Medical School
Benjamin Wesley: Harvard Medical School
Brian Shaw: Harvard Medical School
Edwin Nieblas-Bedolla: Harvard Medical School
Lian Atlas: Harvard Medical School
Annamaria Szabolcs: Harvard Medical School
Anthony J. Iafrate: Harvard Medical School
Mehmet Toner: Harvard Medical School
David T. Ting: Harvard Medical School
Priscilla K. Brastianos: Harvard Medical School
Daniel A. Haber: Harvard Medical School
Shyamala Maheswaran: Harvard Medical School

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-020-20144-w Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-20144-w

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-020-20144-w

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().