BRCA1-IRIS promotes human tumor progression through PTEN blockade and HIF-1α activation Journal Article
| Authors: | Li, A. G.; Murphy, E. C.; Culhane, A. C.; Powell, E.; Wang, H.; Bronson, R. T.; Von, T.; Giobbie-Hurder, A.; Gelman, R. S.; Briggs, K. J.; Piwnica-Worms, H.; Zhao, J. J.; Kung, A. L.; Kaelin, W. G. Jr; Livingston, D. M. |
| Article Title: | BRCA1-IRIS promotes human tumor progression through PTEN blockade and HIF-1α activation |
| 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. © 2018 National Academy of Sciences.All Rights Reserved. |
| Keywords: | controlled study; unclassified drug; oncoprotein; human cell; nonhuman; mouse; gene overexpression; breast cancer; animal experiment; animal model; lung cancer; genetic transcription; tumor xenograft; tumor suppressor gene; gene activation; transcription regulation; cancer cell; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; tumor growth; metastatic breast cancer; hypoxia inducible factor 1alpha; chromosome replication; pten gene; acute myeloid leukemia; pi3k/akt signaling; human; priority journal; article; iris protein; brca1-iris gene; metastatic cell line |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 115 |
| Issue: | 41 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2018-10-09 |
| Start Page: | E9600 |
| End Page: | E9609 |
| Language: | English |
| DOI: | 10.1073/pnas.1807112115 |
| PUBMED: | 30254159 |
| PROVIDER: | scopus |
| PMCID: | PMC6187201 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 November 2018 -- Source: Scopus |
