| 1. |
- Costa, Tânia D F, et al.
(författare)
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PAK4 suppresses RELB to prevent senescence-like growth arrest in breast cancer
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 1-18
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Tidskriftsartikel (refereegranskat)abstract
- Overcoming cellular growth restriction, including the evasion of cellular senescence, is a hallmark of cancer. We report that PAK4 is overexpressed in all human breast cancer subtypes and associated with poor patient outcome. In mice, MMTV-PAK4 overexpression promotes spontaneous mammary cancer, while PAK4 gene depletion delays MMTV-PyMT driven tumors. Importantly, PAK4 prevents senescence-like growth arrest in breast cancer cells in vitro, in vivo and ex vivo, but is not needed in non-immortalized cells, while PAK4 overexpression in untransformed human mammary epithelial cells abrogates H-RAS-V12-induced senescence. Mechanistically, a PAK4 - RELB - C/EBPβ axis controls the senescence-like growth arrest and a PAK4 phosphorylation residue (RELB-Ser151) is critical for RELB-DNA interaction, transcriptional activity and expression of the senescence regulator C/EBPβ. These findings establish PAK4 as a promoter of breast cancer that can overcome oncogene-induced senescence and reveal a selective vulnerability of cancer to PAK4 inhibition.
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| 2. |
- Rabieifar, Parisa, et al.
(författare)
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Normal mammary gland development after MMTV-Cre mediated conditional PAK4 gene depletion
- 2019
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- p21-activated kinases (PAKs) are serine/threonine kinases functioning as downstream effectors of the small GTPases Rac1 and Cdc42. Members of the PAK family are overexpressed in human breast cancer, but their role in mammary gland development is not fully explored. Here we examined the functional role of PAK4 in mammary gland development by creating a mouse model of MMTV-Cre driven conditional PAK4 gene depletion in the mammary gland. The PAK4 conditional knock-out mice were born healthy, with no observed developmental deficits. Mammary gland whole-mounts revealed no defects in ductal formation or elongation of the mammary tree through the fat pad. PAK4 gene depletion also did not alter proliferation and invasion of the mammary epithelium in young virgin mice. Moreover, adult mice gave birth to healthy pups with normal body weight upon weaning. This implies that MMTV-Cre induced gene depletion of PAK4 in mice does not impair normal mammary gland development and thereby provides an in vivo model that can be explored for examination of the potential function of PAK4 in breast cancer.
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| 3. |
- Rabieifar, Parisa
(författare)
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PAK4 in organ development and cancer initiation
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Tumors are complex organs with a unique ecosystem containing tumor cells entangled with various infiltrating cells. Tumors have distinct signaling signatures, which confers upon it the ability to grow in the primary host organ and further disseminate to other parts of the body. Tumors are a heterogeneous mix of sub-clones raised through genetic evolution. Concurrently, strong evidence suggests that nongenetic variables such as developmental cues add to this functional heterogeneity within individual tumors. Interestingly, multiple pathways involved in human organ development are restored and upregulated in various adult cancer. p21-activated kinase 4 (PAK4) is a downstream effector of the Cdc42 and Rac1 small Rho family GTPases. PAK4 is involved in embryonic development, but its expression is also upregulated in different cancer types. Formerly, reverse genetic efforts to study PAK4 have been hampered due to the embryonic lethality under the complete depletion of PAK4. Consequently, multiple conditional Pak4 knockout murine models have been developed to study the possible role of PAK4 in various stages of tissue development. The overall aim of this thesis is to explore the role of PAK4 in breast and pancreas organ development and to dissect its role in the formation of pancreatic ductal adenocarcinoma (PDAC). In paper I, we dissected the role of PAK4 in mammary gland development. Conditional Pak4 gene depletion in the murine mammary gland did not affect this organ’s normal physiology or development. Moreover, Pak4 depletion was dispensable for normal murine pancreas development and whole-body hemostasis maintenance paper II. Therefore, the mouse model developed in paper II was further crossed with the Pdx-Cre; K-rasG12D/+ model to investigate the role of Pak4 in PDAC formation in paper III. We demonstrate in paper III that Pak4 depletion significantly reduces the formation of preneoplastic lesions via inhibition of KrasG12D-driven acinar to ductal reprogramming (ADR). The aforementioned halt is accompanied by increased senescence-like growth arrest and decreased apoptosis. Notably, PAK4 gene expression was higher in human PDAC tumors than the normal tissue, and its protein expression was elevated in human pancreatic intraepithelial neoplasia (PanIN) and PDAC compared with the normal tissues. In sum, this thesis improves our understanding of the role of PAK4 in organ development and provides insight into the possible role of PAK4 in PDAC initiation and progression.
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