Abstract from introduction section of full free text of above trial.
AND below suggests overexpression IS PRESENT IN 50% OF HUMAN BREAST TUMOURS of ALL HISTOLOGICAL TYPES..
What does that mean for Tamoxifen for that group?
RB
http://www.jbc.org/cgi/content/full/279/2/1422
.................Several recent studies have suggested that, in addition to cell motility, Pak1 is also involved in breast cancer progression. Adam et al. (13) have shown a mechanistic role for Pak1 activation in the increased cell invasion of breast cancer cells by heregulin. Furthermore, expression of a kinase-dead Pak1 mutant in the highly invasive breast cancer cell lines MDA-MB-435 and MDA-MB-231 led to stabilization of stress fibers, enhanced cell spreading, and reduction in invasiveness (14). Conversely, hyperactivation of the Pak1 pathway by conditional expression of catalytically active T423E Pak1 in the non-invasive breast cancer cell line MCF-7 promotes cell migration and anchorage-independent growth (15). Furthermore, increased Pak1 activity correlates well with the invasiveness of human breast cancer cells and tumors (15). Emerging data suggest that Pak1 may be overexpressed in human cancers. For example, Pak1 gene amplification has also been reported in ovarian (16) and breast (17) cancers. Furthermore, Pak1 protein has been shown to be up-regulated in ovarian tumors (16) and breast cancer (15, 18, and this study).
More recently, Pak1 has been shown to directly phosphorylate estrogen receptor-{alpha} (ER) at Ser-305 and to promote its transactivation functions (19). Additionally, expression of kinase-active T423E Pak1 transgene in mammary glands induces hyperplasia in the mammary epithelium (19), a phenotype manifested by several other oncogenes including cyclin D1 (20).
Overexpression of cyclin D1 has been noted in over 50% of human breast tumors of all histological types (20-22). Cyclin D1 overexpression is found at the earliest stages of breast cancer progression such as ductal carcinoma in situ and maintained in all stages of the metastasis (23). Accordingly, overexpression of murine mammary tumor virus-cyclin D1 in mammary glands leads to breast cancer (20). The expression of cyclin D1 is regulated by diverse signaling cascades. For example, growth factor-dependent growth stimulation of hematopoietic cells has been shown to be dependent on STAT5 regulation of the cyclin D1 promoter (21). Also, NF-{kappa}B interaction with the NF-{kappa}B binding sites in the cyclin D1 promoter is required for cyclin D1 expression, leading to cell cycle progression. The small GTPase Rac1 signaling has been found to activate cyclin D1 transcription by means of an NF-{kappa}B-dependent pathway in murine NIH3T3 cells (22, 23). In addition, up-regulation of cyclin D1 by ER{alpha} signaling is accompanied by an increased proliferative response in breast cancer cells (24, 25), as ER{alpha}-stimulated proliferation could be effectively blocked by antisense cyclin D1 or by microinjection of anti-cyclin D1 antibodies (25, 26) and reversed by cyclin D1 overexpression (27). Up-regulation of cyclin D1 expression has also been found in hyperplastic mammary glands and proliferative human breast disease (28, 29). Together, these observations suggest that cyclin D1 may constitute an important downstream target of diverse upstream signals, with a role in mammary gland development and tumorigenesis. Despite the widespread role of cyclin D1 in the biology of breast cancer, its involvement in Pak1 signaling, a common point of convergence of growth factor signaling in breast cancer cells, remains unknown...................................