TY - JOUR
T1 - BRCA1-IRIS promotes human tumor progression through PTEN blockade and HIF-1α activation
AU - Li, Andrew G.
AU - Murphy, Elizabeth C.
AU - Culhane, Aedin C.
AU - Powell, Emily
AU - Wang, Hua
AU - Bronson, Roderick T.
AU - Von, Thanh
AU - Giobbie-Hurder, Anita
AU - Gelman, Rebecca S.
AU - Briggs, Kimberly J.
AU - Piwnica-Worms, Helen
AU - Zhao, Jean J.
AU - Kung, Andrew L.
AU - Kaelin, William G.
AU - Livingston, David M.
N1 - Publisher Copyright:
© 2018 National Academy of Sciences.All Rights Reserved.
PY - 2018/10/9
Y1 - 2018/10/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85054778045&partnerID=8YFLogxK
U2 - 10.1073/pnas.1807112115
DO - 10.1073/pnas.1807112115
M3 - Article
C2 - 30254159
AN - SCOPUS:85054778045
SN - 0027-8424
VL - 115
SP - E9600-E9609
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 41
ER -