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Abstract
The Pak4 protein kinase, normally expressed at low level in the mammary gland, is commonly overexpressed in breast cancer. Overexpression of Pak4 transforms mouse mammary epithelial cells in vitro and renders these cells tumorigenic in athymic mice in vivo. Here we show that Pak4 is also required for oncogenic transformation of the human breast cancer cell line MDA-MB-231. These high Pak4-expressing human breast cancer cells form highly disorganized three-dimensional (3D) structures in vitro and readily give rise to orthotopic xenograft tumors in nude mice. We have found that when Pak4 levels are reduced, MDA-MB-231 cells exhibit decreased proliferation and migration in vitro, as well as gross restoration of normal 3D mammary acinar organization, the latter in association with a strong induction of apoptosis. Similarly, Pak4 knockdown suppresses MDA-MB-231 breast xenograft tumor formation in nude mice in vivo. These results indicate that Pak4 has a key role in the oncogenic transformation of breast cells.
Highlights
The Pak family of serine/threonine kinases are important signaling proteins implicated in many cellular functions including cell proliferation, migration and cytoskeletal organization.[1]
Pak[4] is overexpressed in breast cancer cell lines[4,5,9] and in primary human breast tumor and rat mammary tumor samples,[4] but it is barely detectable in normal tissue.[4]
Morphology that were consistent with at least partially reversing the malignant transformation process. These results indicate that Pak[4] has a key role in the oncogenic transformation of breast cells, and support the idea that Pak[4] or Pak4-mediated pathways may become important drug targets for breast cancer treatment
Summary
The Pak family of serine/threonine kinases are important signaling proteins implicated in many cellular functions including cell proliferation, migration and cytoskeletal organization.[1] The Pak family consists of six members. These include group A; Paks 1, 2 and 3, and group B; Paks 4, 5 and 6.1 The Paks have an amino terminal GTPase-binding domain, which can bind to the Rho. GTPases Cdc[42] and Rac, and a carboxyl terminal serine/threonine kinase domain. Amino-acid identity in the GTPase-binding domain and kinase domains, but differ throughout their other domains.[1] Pak[4] has important roles in cell proliferation, survival, cell shape and animal development. The chromosomal region containing Pak4, 19q13.2, is frequently amplified in aggressive breast cancers with basal-like features.[6]
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