View Full Version : Possibility premenopausal overexpressing PAK should not use Tamoxifen...
More possible exceptions to Tamoxifen treatment.
Please use seach re previously posted potential exceptions - high expression Cyclin D - possible gene types etc [A trial suggested there may even be a negative impact etc for high cyclin d expressors].
RB
ABSTRACT
http://www.medpagetoday.com/HematologyOncology/BreastCancer/tb/3314
MedPage Today Action Points
* Advise patients who ask that five years of adjuvant tamoxifen has been regarded as a standard of care for women whose breast tumors are estrogen-receptor positive, but that some women seem to be intrinsically resistant to the drug.
* Note that this study implies that such resistance is due to high levels of a protein whose job it is to activate estrogen receptors.
* Explain that these results raise the possibility that premenopausal breast cancer patients whose tumors overexpress Pak1 may need to be offered alternative endocrine treatment.
[ARTICLE at link gives details rb]
TECHNICAL
1: J Natl Cancer Inst. 2006 May 17;98(10):671-80. Related Articles, Links
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Association between Pak1 expression and subcellular localization and tamoxifen resistance in breast cancer patients.
Holm C, Rayala S, Jirstrom K, Stal O, Kumar R, Landberg G.
Division of Pathology, Department of Laboratory Medicine, Lund University, Malmo, Sweden.
BACKGROUND: p21-activated kinase 1 (Pak1) phosphorylates many proteins in both normal and transformed cells. Its ability to phosphorylate and thereby activate the estrogen receptor alpha (ERalpha) potentially limits the effectiveness of antiestrogen treatment in breast cancer. Here we studied associations between Pak1 expression and subcellular localization in tumor cells and tamoxifen resistance. METHODS: Pak1 protein expression was evaluated in 403 primary breast tumors from premenopausal patients who had been randomly assigned to 2 years of adjuvant tamoxifen or no treatment. Tamoxifen response was evaluated by comparing recurrence-free survival in relation to Pak1 and ERalpha expression in untreated versus tamoxifen-treated patients. Tamoxifen responsiveness of human MCF-7 breast cancer cells that inducibly expressed constitutively active Pak1 or that transiently overexpressed wild-type Pak1 (Wt-Pak1) or Pak1 that lacked functional nuclear localization signals (Pak1DeltaNLS) was evaluated by analyzing cyclin D1 promoter activation and protein levels as markers for ERalpha activation. The response to tamoxifen in relation to Pak1 expression was analyzed in naturally tamoxifen-resistant Ishikawa human endometrial cancer cells. All statistical tests were two-sided. RESULTS: Among patients who had ERalpha-positive tumors with low Pak1 expression, those treated with tamoxifen had better recurrence-free survival than those who received no treatment (hazard ratio [HR] = 0.502, 95% confidence interval [CI] = 0.331 to 0.762; P = .001) whereas there was no difference in recurrence-free survival between treatment groups for patients whose tumors had high cytoplasmic (HR = 0.893, 95% CI = 0.420 to 1.901; P = .769) or any nuclear Pak1 expression (HR = 0.955, 95% CI = 0.405 to 2.250; P = .916). In MCF-7 cells, overexpression of Wt-Pak1, but not of Pak1DeltaNLS, compromised tamoxifen response by stimulating cyclin D1 expression. Treatment of Ishikawa cells with tamoxifen led to an increase in the amount of nuclear Pak1 and Pak1 kinase activity, suggesting that tamoxifen, to some extent, regulates Pak1 expression. CONCLUSIONS: Our data support a role for Pak1, particular Pak1 localized to the nucleus, in ERalpha signaling and in tamoxifen resistance.
PMID: 16705121 [PubMed - in process]
PAK in regulation of cyclin D1
RB
ABSTRACT
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14530270&query_hl=16&itool=pubmed_docsum
1: J Biol Chem. 2004 Jan 9;279(2):1422-8. Epub 2003 Oct 6. Related Articles, Links
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p21-activated kinase-1 signaling mediates cyclin D1 expression in mammary epithelial and cancer cells.
Balasenthil S, Sahin AA, Barnes CJ, Wang RA, Pestell RG, Vadlamudi RK, Kumar R.
Department of Molecular and Cellular Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
p21-activated kinase 1 (Pak1) has been shown recently to induce hyperplasia in the mammary epithelium, a phenotype also manifested by overexpression of cyclin D1, a known indicator of the proliferative stage. Here we investigated the role of the Pak1 pathway in the expression of cyclin D1 using tissue culture models and transgenic mice expressing activated Pak1 in mammary glands. We found that hyperplastic mammary glands from catalytically active Pak1 transgenic mice exhibit a 5- to 7-fold increased expression of cyclin D1 as compared with stage-matched wild-type mice. In addition, Pak1 levels were elevated in human breast tumors and also correlated well with increased cyclin D1 expression. Increased expression of Pak1 in breast cancer cells stimulated cyclin D1 promoter activity, elevated levels of cyclin D1 mRNA, protein, and nuclear accumulation of cyclin D1. Conversely, Pak1 inhibition by an auto-inhibitory peptide (amino acids 83-149) or Pak1 knockdown by short interference RNA markedly reduced the expression of cyclin D1, suggesting a requirement of a functional Pak1 pathway for optimal expression of cyclin D1. Results from deletion and mutant analysis indicate that Pak1 regulates cyclin D1 transcription by means of an NF-kappaB-dependent pathway. Together, these findings suggest a model wherein Pak1 regulation of cyclin D1 expression might involve an NF-kappaB-dependent pathway and that hyperplasia in the mammary glands of Pak1-TG mice may be associated, at least in part, with the up-regulation of cyclin D1, and that Pak1 is up-regulated in human breast tumors.
PMID: 14530270 [PubMed - indexed for MEDLINE]
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...................................
Curcumin per below inhibits cycin D and P21 (PAK)
1: Ann N Y Acad Sci. 2005 Nov;1056:206-17. Related Articles, Links
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Curcumin: getting back to the roots.
Shishodia S, Sethi G, Aggarwal BB.
Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Box 143, 1515 Holcombe Boulevard, Houston, TX 77030. aggarwal@mdanderson.org.
The use of turmeric, derived from the root of the plant Curcuma longa, for treatment of different inflammatory diseases has been described in Ayurveda and in traditional Chinese medicine for thousands of years. The active component of turmeric responsible for this activity, curcumin, was identified almost two centuries ago. Modern science has revealed that curcumin mediates its effects by modulation of several important molecular targets, including transcription factors (e.g., NF-kappaB, AP-1, Egr-1, beta-catenin, and PPAR-gamma), enzymes (e.g., COX2, 5-LOX, iNOS, and hemeoxygenase-1), cell cycle proteins (e.g., cyclin D1 and p21), cytokines (e.g., TNF, IL-1, IL-6, and chemokines), receptors (e.g., EGFR and HER2), and cell surface adhesion molecules. Because it can modulate the expression of these targets, curcumin is now being used to treat cancer, arthritis, diabetes, Crohn's disease, cardiovascular diseases, osteoporosis, Alzheimer's disease, psoriasis, and other pathologies. Interestingly, 6-gingerol, a natural analog of curcumin derived from the root of ginger (Zingiber officinalis), exhibits a biologic activity profile similar to that of curcumin. The efficacy, pharmacologic safety, and cost effectiveness of curcuminoids prompt us to "get back to our roots."
PMID: 16387689 [PubMed - in process]
NSAIDs inhibit the serine-threonine kinase p21-activated protein kinase 1 (Pak1)
Is the implication that P21 is inflamation related.
How does impact of omega sixes and three six balance on inflamatory pathways fit in?
RB
1: Blood. 2005 Mar 1;105(5):2042-8. Epub 2004 Oct 28. Related Articles, Links
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Nonsteroidal anti-inflammatory drugs inhibit a Fyn-dependent pathway coupled to Rac and stress kinase activation in TCR signaling.
Paccani SR, Patrussi L, Ulivieri C, Masferrer JL, D'Elios MM, Baldari CT.
Department of Evolutionary Biology, University of Siena, Siena, Via Aldo Moro 2, 53100 Siena, Italy.
In addition to their anti-inflammatory properties, nonsteroidal anti-inflammatory drugs (NSAIDs) harbor immunosuppressive activities related to their capacity both to inhibit cyclooxygenases (COXs) and to act as peroxisome proliferator-activated receptor (PPAR) ligands. We have previously shown that the stress-activated kinase p38 is a selective target of NSAIDs in T cells. Here we have investigated the effect of NSAIDs on the signaling pathway triggered by the T-cell antigen receptor (TCR) and leading to stress kinase activation. The results show that nonselective and COX-1-selective NSAIDs also block activation of the stress kinase c-Jun N-terminal kinase (JNK) and that prostaglandin-E2 (PGE2) reverses this block and enhances TCR-dependent JNK activation. Analysis of the activation state of the components upstream of p38 and JNK showed that NSAIDs inhibit the serine-threonine kinase p21-activated protein kinase 1 (Pak1) and the small guanosine 5'-triphosphatase (GTPase) Rac, as well as the Rac-specific guanine nucleotide exchanger, Vav. Furthermore, activation of Fyn, which controls Vav phosphorylation, is inhibited by NSAIDs, whereas activation of lymphocyte-specific protein tyrosine kinase (Lck) and of the Lck-dependent tyrosine kinase cascade is unaffected. Accordingly, constitutively active Fyn reverses the NSAID-dependent stress kinase inhibition. The data identify COX-1 as an important early modulator of TCR signaling and highlight a TCR proximal pathway selectively coupling the TCR to stress kinase activation.
PMID: 15514010 [PubMed - indexed for MEDLINE]
Another natural agent to keep an eye on.
RB
ABSTRACT
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16418572&query_hl=16&itool=pubmed_docsum
1: Cancer Biol Ther. 2006 Mar;5(3):305-309. Epub 2006 Mar 12. Related Articles, Links
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Sichuan Pepper Extracts Block the PAK1/Cyclin D1 Pathway and the Growth of NF1-Deficient Cancer Xenograft in Mice.
Hirokawa Y, Nheu T, Grimm K, Mautner V, Maeda S, Yoshida M, Komiyama K, Maruta1 H.
Ludwig Institute for Cancer Research, Parkville/Melbourne, Australia.
There is increasing evidence that more than 70% of cancers including pancreatic, breast and prostate cancers as well as neurofibromatosis (NF) are highly addicted to abnormal activation of the Ser/Thr kinase PAK1 for their growth. So far FK228 is the most potent among the HDAC (histone deacetylase) inhibitors that block the activation of both PAK1 and another kinase AKT, downstream of PI-3 kinase. However, FK228 is still in clinical trials (phase 2) for a variety of cancers (but not for NF as yet), and not available for most cancer/NF patients. Thus, we have been exploring an alternative which is already in the market, and therefore immediately useful for the treatment of those desperate cancer/NF patients. Here we provide the first evidence that extracts of Chinese/ Japanese peppercorns (Zanthoxyli Fructus) from the plant Zanthoxylum piperitum called "Hua Jiao"/"Sansho", block selectively the key kinase PAK1, leading to the downregulation of cyclin D1. Unlike FK228, these extracts do not inhibit AKT activation at the concentrations that block either cancer growth or PAK1 activation. The Chinese pepper extract selectively inhibits the growth of NF1-deficient malignant peripheral nerve sheath tumor (MPNST) cells, without affecting the growth of normal fibroblasts, and suppresses the growth of NF1-deficient human breast cancer (MDA-MB-231) xenograft in mice. Our data suggest that these peppercorn extracts would be potentially useful for the treatment of PAK1-dependent NF such as MPNST, in addition to a variety of PAK1-dependent cancers including breast cancers.
PMID: 16418572 [PubMed - as supplied by publisher]
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