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Proc Natl Acad Sci U S A. 2018 Oct 9;115(41):E9600-E9609. doi: 10.1073/pnas.1807112115. Epub 2018 Sep 25.

BRCA1-IRIS promotes human tumor progression through PTEN blockade and HIF-1α activation.

Author information

1
Department of Genetics, Harvard Medical School, Boston, MA 02115; andrew_li@dfci.harvard.edu david_livingston@dfci.harvard.edu.
2
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215.
3
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215.
4
Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115.
5
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
6
Department of Genetics, Harvard Medical School, Boston, MA 02115.
7
Department of Pathology, Harvard Medical School, Boston, MA 02115.
8
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215.
9
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215.
10
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
11
Howard Hughes Medical Institute, Chevy Chase, MD 20815.

Abstract

BRCA1 is an established breast and ovarian tumor suppressor gene that encodes multiple protein products whose individual contributions to human cancer suppression are poorly understood. BRCA1-IRIS (also known as "IRIS"), an alternatively spliced BRCA1 product and a chromatin-bound replication and transcription regulator, is overexpressed in various primary human cancers, including breast cancer, lung cancer, acute myeloid leukemia, and certain other carcinomas. Its naturally occurring overexpression can promote the metastasis of patient-derived xenograft (PDX) cells and other human cancer cells in mouse models. The IRIS-driven metastatic mechanism results from IRIS-dependent suppression of phosphatase and tensin homolog (PTEN) transcription, which in turn perturbs the PI3K/AKT/GSK-3β pathway leading to prolyl hydroxylase-independent HIF-1α stabilization and activation in a normoxic environment. Thus, despite the tumor-suppressing genetic origin of IRIS, its properties more closely resemble those of an oncoprotein that, when spontaneously overexpressed, can, paradoxically, drive human tumor progression.

KEYWORDS:

BRCA1-IRIS; HIF-1α; PTEN; metastasis

PMID:
30254159
PMCID:
PMC6187201
DOI:
10.1073/pnas.1807112115
[Indexed for MEDLINE]
Free PMC Article

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