Normal mammary gland development after MMTV-Cre mediated conditional PAK4 gene depletion

Rabieifar, Parisa; Zhuang, Ting; Costa, Telma; Zhao, Miao; Strömblad, Staffan

doi:10.1101/658583

Cited by 2 publications

(1 citation statement)

References 49 publications

(60 reference statements)

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“…The H&E images of mammary glands show significantly reduced number of ducts (highlighted by arrows) in N-WASP MKO compared to N-WASP MHet (Figure 3.5). The ducts were quantified using Image J by using the counter plugin tool as described by [200,201]. Keratin 5 is expressed in the myoepithelial cells, which are present on the outer layer of the mammary duct touching the basement membrane [88].…”

Section: N-wasp Knockout Mammary Glands Show Significantly Reduced Nu...mentioning

confidence: 99%

Role of N-WASP in cell proliferation : implication for organ development and cancer

Verma¹

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N-WASP regulates actin cytoskeleton and plays key roles in many cellular processes such as cell-proliferation, cell-adhesion, cell-migration and endocytosis which are essential for normal cell physiology. Development of organs such as lungs and mammary glands requires elongation and branching of epithelial tissues which are critically depended on apical-basal polarity, cell adhesion, cell proliferation and interactions with the extracellular matrix proteins. N-WASP has also been shown to regulate cell invasion and EMT (Epithelial to Mesenchymal transition), which are often upregulated during cancer progression. Studies show that N-WASP expression is reduced in breast, colorectal and stage I lung cancer, however its role in lung cancer is not well characterized.It is known from developmental studies that majority of mammary gland development occurs during the adult stage in which extensive branching and duct elongation occurs.Ablation of N-WASP in mice using K5-Cre resulted in significantly decreased number of ducts and sub-ductal branches in the mammary gland. Immunohistochemistry showed significantly reduced number of PCNA positive cells in N-WASP KO mammary glands suggesting reduced proliferation. Moreover, N-WASP KO mammary glands also displayed significantly higher collagen content around the mammary ducts suggesting reduced invasion these ducts. In-vitro experiments with N-WASP knockdown, normal mammary epithelial cell line, MCF10A (MCF10A KD ) also showed reduced proliferation, migration, invasion and cell-cell adhesion. Re-expression of N-WASP in MCF10A KD rescued the proliferation defect suggesting N-WASP's direct role in cell proliferation.

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Section: N-wasp Knockout Mammary Glands Show Significantly Reduced Nu...mentioning

confidence: 99%

Role of N-WASP in cell proliferation : implication for organ development and cancer

Verma¹

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PAK4 suppresses RELB to prevent senescence-like growth arrest in breast cancer

et al. 2019

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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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Normal mammary gland development after MMTV-Cre mediated conditional PAK4 gene depletion

Cited by 2 publications

References 49 publications

Role of N-WASP in cell proliferation : implication for organ development and cancer

Role of N-WASP in cell proliferation : implication for organ development and cancer

PAK4 suppresses RELB to prevent senescence-like growth arrest in breast cancer

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