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(throwing yet another wrench in here....)
(I wonder, since Pak1 affects ER, I wonder if it affects PR and/or HER2 at all, or if PR and/or HER2 affect Pak1.):
Increased protein expression may explain tamoxifen resistance
Reuters Health
Posting Date: May 16, 2006
Last Updated: 2006-05-16 16:00:20 -0400 (Reuters Health)
NEW YORK (Reuters Health) - Pak1 (p21-activated kinase-1), a protein that activates estrogen receptors (ER) and localizes in the nucleus of breast tumors, appears to induce tamoxifen resistance in ER-positive cancers, investigators report.
Many patients with ER-positive tumors either do not respond to tamoxifen treatment or develop resistance to the agent. Pak1 is known to phosphorylate proteins, including ER-alpha. Studies have suggested that Pak1 phosphorylation of ER-alpha activates the receptor and modulates its response to estrogens and antiestrogens.
Dr. Goran Landberg, from Lund University in Malmo, Sweden, and associates evaluated Pak1 and ER-alpha expression in 403 primary breast tumors from premenopausal patients who had been randomly assigned to tamoxifen or no tamoxifen following surgery and radiation therapy. They report their findings in the Journal of the National Cancer Institute for May 17.
The researchers assessed Pak1 levels in ER-alpha-positive tumor tissue by immunohistochemical staining with a polyclonal antibody against Pak1. Their results showed that 19% of tumors had high cytoplasmic Pak1 expression, and 13% were positive for nuclear Pak1 staining.
The investigators observed that lobular breast cancers were more likely to be Pak1 negative (78%) compared with ductal (50%) or medullary (30%) breast cancers. Pak1 staining was also associated with higher histologic grade and increased tumor cell proliferation, indicating a more malignant phenotype.
Dr. Landberg's group also found that among patients who were treated with tamoxifen, tumors with the lowest expression of Pak1 had longer recurrence-free survival than patients not treated with tamoxifen.
In contrast, among patients with high expression of Pak1, tamoxifen had no effect on recurrence-free survival.
In the untreated control group, which included both ER-negative and ER-positive tumors, Pak1 staining intensity in the cytoplasm of the nucleus was not associated with outcome.
"Our results raise the possibility that premenopausal breast cancer patients whose tumors overexpress Pak1 most likely will not respond to tamoxifen and may need to be offered alternative endocrine treatment," Dr. Landberg's team maintains.
They also suggest that "therapies that target Pak1 expression or activity may therefore represent a strategy to increase the endocrine treatment response in breast cancer."
In a related editorial, Dr. V. Craig Jordan, from Fox Chase Cancer Center in Philadelphia, further discusses the ramifications of the phosphorylation network in cancer cells.
He believes that knocking out Pak1 activity would not overcome tamoxifen resistance, but that "a combined attack at multiple upstream targets would be more likely to succeed."
"Regardless," he concludes, "the clinical correlations reported by Holm et al. indicate that packing tumor cell nuclei with Pak can perturb tamoxifen's action. The tumor, once 'Paked up,' has no alternative but to grow."
J Natl Cancer Inst 2006;98:657-659,671-680.
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