Metastatic potential of 21T human breast cancer cells depends on Akt/protein kinase B activation.
Most cancer lethality is caused by metastasis. To gain insight into the molecular basis of tumor progression to metastasis, we used the 21T series of human mammary epithelial cells obtained by successive biopsies from one breast cancer patient. The c-erbB2 gene is amplified and overexpressed in each of three 21T tumor lines. The erbB receptor tyrosine kinase-activated phosphatidylinositol 3-kinase/Akt signaling cascade is crucial for the development and maintenance of epithelial cells, and dysregulation of this pathway is frequently associated with cellular transformation and cancer. For Akt to be fully activated, Ser(473) on its COOH terminus needs to be phosphorylated. We detected more Ser(473) Akt phosphorylation in MT cells, derived from a pleural effusion, compared with cells from the primary tumor. This phosphorylation has recently been shown to be catalyzed by mammalian target of rapamycin (mTOR)/rictor kinase. By using genetic and pharmacologic activators and inhibitors, we showed that Ser(473) Akt phosphorylation is more sensitive to mTOR/rictor inhibition in metastatic tumor cells than normal mammary epithelial and primary tumor cells. The mTOR/rictor kinase activity was indispensable for both Ser(473) Akt phosphorylation and migration of metastatic MT2 cells. In addition, a large decrease of protein phosphatase PH domain leucine-rich repeat protein phosphatase (PHLPP) was found, which could be responsible for the overexpression of Ser(473) Akt in MT cells. Our data indicate that these breast cancer cells acquire new vulnerabilities, rictor and PHLPP, which might provide an Achilles' heel for therapeutic intervention of breast cancer metastasis.
Qiao
Meng
M
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02135, USA. meng_qiao@dfci.harvard.edu
Iglehart
J Dirk
JD
Pardee
Arthur B
AB
D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000201:enzymology / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D009362:Neoplasm Metastasis; D020890:Neuregulin-1; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000096:biosynthesis / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism
D002352:Carrier Proteins; D020890:Neuregulin-1; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D010749:Phosphoprotein Phosphatases; D051057:Proto-Oncogene Proteins c-akt; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D018719:Erb-b2 Receptor Tyrosine Kinases; C492571:RICTOR protein, human; C400601:PHLPP1 protein, human