p21-activated kinase signaling in breast cancer

Abstract

The p21-activated kinases signal through a number of cellular pathways fundamental to growth, differentiation and apoptosis. A wealth of information has accumulated at an impressive pace in the recent past, both with regard to previously identified targets for p21-activated kinases that regulate the actin cytoskeleton and cellular stress pathways and with regard to newly identified targets and their role in cancer. Emerging data also provide new clues towards a previously unappreciated link between these various cellular processes. The present review attempts to provide a quick tutorial to the reader about the evolving significance of p21-activated kinases and small GTPases in breast cancer, using information from mouse models, tissue culture studies, and human materials.

Figure 1

p21-activated kinase (PAK) as a signaling nodule in breast cancer cells. Mechanisms of PAK activation and downstream physiological effects of PAKs are indicated, emphasizing the multiple functions of PAKs in cells. PAKs act upstream of several effectors. The effectors and the outcomes they influence are shown in this schematic. DLC1, dynein light chain 1; ER, estrogen receptor; MAPK, mitogen-activated protein kinase; PGAM, phosphoglyceraldehyde mutase; PGM, phosphoglucomutase; VEGF, vascular endothelial growth factor.

Figure 2

Known phenotypic changes in mammary epithelium and breast cancer. (a) Overactivation of p21-activated kinase Pak1 in mouse mammary gland induced hyperplasia. While the wild-type (WT) mouse mammary gland has only one single layer of cells (left panel), the mammary gland of the Pak1-TG mice reveals many layers of cells protruding into the lumen of alveoli (right panel). (b) Immunohistochemical detection of Pak1 in normal and breast tumor sections. Left panel, normal section showing weak cytoplasmic Pak1 expression; right panel, tumor section showing an intense cytoplasmic staining compared with the normal section.

Figure 3

A schematic model of p21-activated kinase (PAK) action in the absence of estrogen in breast cancer cells. A simplified summary of the cellular events in which regulation of cancer-related events by PAKs has been implicated. Both the N-termini and C-termini of PAK can interact with various signaling components and thus promote specific changes required for cells to acquire a cancerous and metastatic phenotype. Broken lines, proposed regulation. ER, estrogen receptor; PKA, protein kinase A.