p21-activated kinase signaling in breast cancer

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

PAK thread from amoeba to mammals

The p21-activated kinases (PAKs) are signaling nodes that play a crucial role in cellular processes including cell motility, differentiation, survival, gene transcription and hormone signaling. PAKs are highly conserved family of serine threonine kinases that act as effector for small GTPases Rac and Cdc42. Most of our knowledge about PAK functions has been derived from genetic approaches in lower organisms and many of these functions are similar to that seen in mammalian cells. In this review, we have summarized the extensive information generated in lower eukaryotes and very briefly discussed the current status of PAKs in humans

Extranuclear coactivator signaling confers insensitivity to tamoxifen

PURPOSE: Tamoxifen is one of many standard therapeutic option currently available for estrogen receptor-alpha (ER)-positive breast cancer patients. Emerging data have suggested that levels of ER coregulatory proteins play a significant role in acquiring resistance to anti-estrogen action. It has been suggested that high levels of ER coactivators and ER localization may enhance the estrogen agonist activity of tamoxifen and contribute to tamoxifen resistance. EXPERIMENTAL DESIGN: In an effort to understand the impact of non-genomic signaling and its contribution to hormone resistance in a whole-animal setting, we generated a transgenic mouse expressing a cytoplasmic version of PELP1 mutant defective in its nuclear translocation (PELP1-cyto) and implanted these mice with tamoxifen pellets to assess its responsiveness. RESULTS: We show that mammary glands from these mice developed widespread hyperplasia with increased cell proliferation and enhanced activation of mitogen-activated protein kinase (MAPK) and AKT at as early as 12 weeks of age. Treatment with tamoxifen did not inhibit this hyperplasia; instead, such treatment exaggerated hyperplasia with an enhanced degree of alteration indicative of hypersensitivity to tamoxifen. Analysis of molecular markers in the transgenic mammary glands from the tamoxifen-treated transgenic mice showed higher levels of proliferation markers PCNA and activated MAPK, than in untreated PELP1-cyto mice. We also found that nude mice with MCF-7/PELP1-cyto tumor xenografts did not respond to tamoxifen. Using immunohistochemical analysis, we found that 43% of human breast tumor samples had high levels of cytoplamic PELP1, which shows a positive correlation between tumor grade and proliferation. Patients whose tumors had high levels of cytoplasmic PELP1 exhibited a tendency to respond poorly to tamoxifen, compared with patients whose tumors had low levels of cytoplamic PELP1. CONCLUSIONS: These findings suggest that PELP1 localization could be used as a determinant of hormone sensitivity or vulnerability. The establishment of the PELP1-cyto transgenic mouse model is expected to facilitate the development of preclinical approaches for effective intervention of breast tumors using cytoplasmic coregulators and active non-genomic signaling

Functional regulation of oestrogen receptor pathway by the dynein light chain 1

Overexpression and phosphorylation of dynein light chain 1 (DLC1) have been shown to promote the growth of breast cancer cells. However, the role of DLC1 in the action of the oestrogen receptor (ER) remains unknown. Here, we found that oestrogen induces the transcription and expression of DLC1. DLC1 facilitated oestrogen-induced ER transactivation and anchorage-independent growth of breast cancer cells. We show that DLC1 interacts with ER, and such interaction is required for the transactivation-promoting activity of DLC1. Further, DLC1 expression led to enhanced recruitment of the DLC1–ER complex to the ER-target gene chromatin. Conversely, DLC1 downregulation compromised the ER-transactivation activity and also its nuclear accumulation, suggesting a potential chaperone-like activity of DLC1 in the nuclear translocation of ER. Together, these data define an unexpected upregulation of DLC1 by oestrogen and a previously unrecognized DLC1–ER interaction in supporting and amplifying ER-initiated cellular responses in breast cancer cells