Estrogen regulation of Pak1 and FKHR pathways in breast cancer cells

@article{Mazumdar2003EstrogenRO,
  title={Estrogen regulation of Pak1 and FKHR pathways in breast cancer cells},
  author={Abhijit Mazumdar and Rakesh Kumar},
  journal={FEBS Letters},
  year={2003},
  volume={535}
}

Synergistic Activation of ERα by Estrogen and Prolactin in Breast Cancer Cells Requires Tyrosyl Phosphorylation of PAK1.

The mechanisms underlying the hormone-induced activation of estrogen receptor (ERα, ESR1) are investigated and it is suggested that ligand-independent activation of ERα through PRL/PAK1 may impart resistance to anti-estrogen therapies.

Inhibition of the Rho GTPase, Rac1, decreases estrogen receptor levels and is a novel therapeutic strategy in breast cancer.

Rac1 enhanced ERα transcriptional activity in breast cancer cells and EHT 1864 decreased activity of the promoter of the ERα gene resulting in down-regulation of ERα mRNA and protein levels, suggesting that Rac1 may prove to be a therapeutic target.

P21-activated kinase 1 regulation of estrogen receptor-alpha activation involves serine 305 activation linked with serine 118 phosphorylation.

It is suggested that Pak1 signaling-dependent activation of ER-S305 leads to an enhanced S118 phosphorylation presumably due to a conformational change, and such structural modifications may participate in the development of tamoxifen resistance.

Akt-Induced Tamoxifen Resistance is Associated with Altered FKHR Regulation

It is found that MCF-7 breast cancer cell lines expressing a constitutively active Akt are able to proliferate under reduced estrogen conditions and are resistant to the growth inhibitory effects of tamoxifen, both in vitro as well as in vivo in xenograft models.

Tyrosyl phosphorylated serine-threonine kinase PAK1 is a novel regulator of prolactin-dependent breast cancer cell motility and invasion.

Tyrosyl phosphorylated PAK1 stimulates invasion of breast cancer cells in response to PRL and three-dimensional (3D) collagen IV via transcription and secretion of MMP-1 and MMP3 in a MAPK-dependent manner.

PAK1 translocates into nucleus in response to prolactin but not to estrogen.

Active p21-activated kinase 1 rescues MCF10A breast epithelial cells from undergoing anoikis.

A role for activated PAK1 in the suppression of anoikis in MCF10A epithelial cells is supported and appears to occur early in the apoptotic cascade as expression of dominant-negative PAK 1 increased the cleavage of the upstream caspase 9, while constitutively activePAK1 inhibited caspases 9 activation.

Association between Pak1 expression and subcellular localization and tamoxifen resistance in breast cancer patients.

A role for Pak1, particular Pak1 localized to the nucleus, in ERalpha signaling and in tamoxifen resistance is supported, suggesting that tamoxIFen, to some extent, regulates Pak1 expression.

PAK signaling in cancer

Although PAKs are not mutated in cancers, they are overexpressed, hyperactivated or amplified in several human tumors and their role in cell transformation make them attractive therapeutic targets.

A Derivative of Differentiation-Inducing Factor-3 Inhibits PAK1 Activity and Breast Cancer Cell Proliferation

PAK1 is proposed as DIF-3(+1) target mediating its anti-proliferative effect as well as some derivatives of DIFs and their derivatives on PAK1, a key serine-threonine kinase, which is activated by multiple ligands and regulates cell proliferation.
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