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Loss of ASAP1 in the MMTV-PyMT model of luminal breast cancer activates AKT, accelerates tumorigenesis, and promotes metastasis

ASAP1 is a multi-domain adaptor protein that regulates cytoskeletal dynamics, receptor recycling and intracellular vesicle trafficking. Its expression is associated with poor prognosis in a variety of cancers, and can promote cell migration, invasion and metastasis. Although amplification and expres...

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Main Authors: Schreiber, Caroline (Author) , Gruber, Annette (Author) , Roßwag, Sven (Author) , Saraswati, Supriya (Author) , Harkins, Shannon (Author) , Thiele, Wilko (Author) , Foroushani, Zahra Hajian (Author) , Munding, Natalie (Author) , Schmaus, Anja (Author) , Rothley, Melanie (Author) , Dimmler, Arno (Author) , Tanaka, Motomu (Author) , Garvalov, Boyan K. (Author) , Sleeman, Jonathan P. (Author)
Format: Article (Journal)
Language:English
Published: 1 May 2022
In: Cancer letters
Year: 2022, Volume: 533, Pages: 1-12
ISSN:1872-7980
DOI:10.1016/j.canlet.2022.215600
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.canlet.2022.215600
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0304383522000751
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Author Notes:Caroline Schreiber, Annette Gruber, Sven Roßwag, Supriya Saraswati, Shannon Harkins, Wilko Thiele, Zahra Hajian Foroushani, Natalie Munding, Anja Schmaus, Melanie Rothley, Arno Dimmler, Motomu Tanaka, Boyan K. Garvalov, Jonathan P. Sleeman
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Summary:ASAP1 is a multi-domain adaptor protein that regulates cytoskeletal dynamics, receptor recycling and intracellular vesicle trafficking. Its expression is associated with poor prognosis in a variety of cancers, and can promote cell migration, invasion and metastasis. Although amplification and expression of ASAP1 has been associated with poor survival in breast cancer, we found that in the autochthonous MMTV-PyMT model of luminal breast cancer, ablation of ASAP1 resulted in an earlier onset of tumor initiation and increased metastasis. This was due to tumor cell-intrinsic effects of ASAP1 deletion, as ASAP1 deficiency in tumor, but not in stromal cells was sufficient to replicate the enhanced tumorigenicity and metastasis observed in the ASAP1-null MMTV-PyMT mice. Loss of ASAP1 in MMTV-PyMT mice had no effect on proliferation, apoptosis, angiogenesis or immune cell infiltration, but enhanced mammary gland hyperplasia and tumor cell invasion, indicating that ASAP1 can accelerate tumor initiation and promote dissemination. Mechanistically, these effects were associated with a potent activation of AKT. Importantly, lower ASAP1 levels correlated with poor prognosis and enhanced AKT activation in human ER+/luminal breast tumors, validating our findings in the MMTV-PyMT mouse model for this subtype of breast cancer. Taken together, our findings reveal that ASAP1 can have distinct functions in different tumor types and demonstrate a tumor suppressive activity for ASAP1 in luminal breast cancer.
Item Description:Online verfügbar: 15. Februar 2022, Artikelversion: 22. Februar 2022
Gesehen am 11.03.2024
Physical Description:Online Resource
ISSN:1872-7980
DOI:10.1016/j.canlet.2022.215600

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