Dysregulation of phosphatidylinositol 3‐kinase and downstream effectors in human breast cancer

Abstract

Phosphatidylinositol 3-kinase (PI3-K) is a growth factoractivated transforming lipid (and protein) kinase, involved in cell motility and invasion, that has multiple effectors. Relatively little is known about its expression and enzymatic activity in human breast cancer. Since growth factor receptors are amplified in breast cancer, and the tumor suppressor PTEN may be mutated in human breast cancer, it was hypothesized that PI3-K and its downstream effectors would be activated in this disease. In 11 resected tumors analyzed for expression of this kinase, a mean 3-fold increase in protein expression was observed over the corresponding adjacent control tissue. Using an in vitro lipid kinase assay of the immunoprecipitated PI3-K protein, a greater than 2-fold increase in activation was observed. These changes were observed in the absence of an activation of either protein kinase B (PKB, akt1) or p70 S6 kinase (p70 S6K). However, p21-activated kinase (Pak), p38 mitogen-activated protein kinase (p38 MAPK) and mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK 2) were all overexpressed and demonstrated increased enzyme activity. It may be concluded that aberrant mitogenic signaling in human breast cancer in vivo involves Pak, p38 MAPK and MAPKAPK2 downstream of PI3-K, but neither of PKB or p70 S6K. It is proposed that this pathway may serve as a useful targeting nexus for investigation of small molecule inhibitors in human breast cancer.

Differential targeting of protein kinase B in cell death induced by sulindac and its metabolite sulindac sulfide

“…We conclude that these findings may be of medical importance, as a number of the components in the PI3-kinase pathway have been demonstrated to be dysregulated in human cancers (52)(53)(54). Therefore, based upon the observation that overexpression of an integral component in the PI3-kinase pathway, PKB, had no effect on sulindac sulfide-induced cell death, whereas the effects of sulindac were dramatically blunted, we propose that treatment with the former may be an effective adjuvant therapy.…”

Dysregulation of integrin-linked kinase (ILK) signaling in colonic polyposis

“…All sections were incubated overnight at RT with the anti-ILK (1 : 100) antibody. Staining was completed according to Salh et al (1999). Representative cases are shown.…”

Crosstalk between steroid receptors and the c-Src-receptor tyrosine kinase pathways: implications for cell proliferation

“…Like ER, the phosphorylated PR has increased sensitivity to lower levels of ligand , and EGF and progesterone treatment of breast cancer cells synergistically stimulate expression of genes such as cyclin D1 and E that are critical for proliferation . Because breast tumors often have elevated levels of MAPK activity (Salh et al, 1999), activation of ERs and PRs independent of ligands could occur in these cancers, contributing to receptor-stimulated gene expression and cell growth even in the absence of steroids.…”