The protein kinase Pak4 disrupts mammary acinar architecture and promotes mammary tumorigenesis

Abstract

The Pak4 serine/threonine kinase is highly expressed in many cancer cell lines and human tumors. While several studies have addressed the role for Pak4 in transformation of fibroblasts, most human cancers are epithelial in origin. Epithelial cancers are associated not only with changes in cell growth, but also with changes in the cellular organization within the three dimensional (3D) architecture of the affected tissues. Here we used immortalized mouse mammary epithelial cells (iMMECs) as a model system to study the role for Pak4 in mammary tumorigenesis. iMMECs are an excellent model system for studying breast cancer they can grow in 3D-epithelial cell culture, where they form acinar structures that recapitulate in vivo mammary morphogenesis. While Pak4 is expressed at low levels in wild type iMMECs, it is overexpressed in response to oncogenes, such as oncogenic Ras and Her2/neu. Here we found that overexpression of Pak4 in iMMECs leads to changes in 3D acinar architecture that are consistent with oncogenic transformation. These include decreased central acinar cell death, abrogation of lumen formation, cell polarity alterations, and deregulation of acinar size and cell number. Furthermore, iMMECs overexpressing Pak4 form tumors when implanted into the fat pads of athymic mice. Our results suggest that overexpression of Pak4 triggers events that are important for the transformation of mammary epithelial cells. This is likely to be due to the ability of Pak4 to inhibit apoptosis and promote cell survival, and thus subsequent uncontrolled proliferation, and to its ability to deregulate cell shape and polarity.

Immuno Expression of PAKs in Actinic Cheilitis and in Lip Squamous Cell Carcinoma

“…Therefore, it might be understood that PAK4/5/6 overexpression is absent in cells of LSCC that survive and evade apoptosis. This in contrast with data from literature showing the role of PAK activation and amplification in promoting tumorigenesis, cytoskeletal organization, survival of tumor cells and cancer progression [21][22][23].…”

Increased expression of p21-activated kinase 4 in adenomyosis and its regulation of matrix metalloproteinase-2 and -9 in endometrial cells

“…Many studies have reported Pak4 overexpression in human cancer cell lines, including breast, pancreas, colon, and ovary (7)(8)(9)(10), highlighting the essential role of Pak4 in promoting tumorigenesis and oncogenic transformation by regulating cell invasion, survival, and proliferation. Furthermore, several studies have demonstrated that increased expression of Pak4 is correlated with tumor progression or metastasis (10,11).…”

P21 activated kinases

“…The acini become abnormally large, and their lumens never become completely empty. They have a larger layer of epithelial cells surrounding the lumens, and the cells within the structures have increased levels of cell proliferation and decreased levels of apoptosis, 130 Many of these abnormalities are reminiscent of changes that occur during pre-cancerous conditions and early tumorigenesis. Some of the changes, such as the partial filling of the luminal space with cells, are reminiscent of atypical hyperplasia and DCIS.…”

“…Some of the changes, such as the partial filling of the luminal space with cells, are reminiscent of atypical hyperplasia and DCIS. 132 When iMMECs transfected with wild-type PAK4 are implanted into the mammary fat pads of mice, the mice develop mammary tumors at a high frequency, 130 indicating that wildtype PAK4 can be a driving force in oncogenic transformation of mammary cells. Oncogenes such as ErbB2 and oncogenic Ras also cause oncogenic transformation of iMMECs.…”

“…123 The mouse mammary epithelial cell line iMMEC has been used as a model to study the role for PAK4 in breast cancer. 130 iMMECs can be grown in 3D culture conditions where they grow into spherical acini that resemble the acinar structures that form in normal non-cancerous breast epithelia. 131 As is the case in normal mammary epithelium, wild-type iMMECs have nearly undetectable levels of PAK4.…”