Human mammary epithelial cell transformation through the activation of phosphatidylinositol 3-kinase.
Recent studies have demonstrated that introduction of hTERT in combination with SV40 large T antigen (LT), small t antigen (st), and H-rasV12 suffices to transform many primary human cells. In human mammary epithelial cells (HMECs) expressing elevated c-Myc, activated H-Ras is dispensable for anchorage-independent growth. Using this system, we show that st activates the PI3K pathway and that constitutive PI3K signaling substitutes for st in transformation. Moreover, using constitutively active versions of Akt1 and Rac1, we show that these downstream pathways of PI3K synergize to achieve anchorage-independent growth. At lower levels of c-myc expression, activated PI3K also replaces st to complement H-rasV12 and LT and confers both soft agar growth and tumorigenicity. However, elevated c-myc expression cannot replace H-rasV12 for tumorigenesis. These observations begin to define the pathways perturbed during the transformation of HMECs.
Zhao
Jean J
JJ
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Gjoerup
Ole V
OV
Subramanian
Romesh R
RR
Cheng
Yuan
Y
Chen
Wen
W
Roberts
Thomas M
TM
Hahn
William C
WC
D000362:Agar / Q000378:metabolism; D017398:Alternative Splicing; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D005822:Genetic Vectors; D006801:Humans; D015151:Immunoblotting; D042361:Mammary Glands, Human / Q000166:cytology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D013997:Time Factors; D014162:Transfection; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D000362:Agar; D018076:DNA, Complementary; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc; D020830:rac1 GTP-Binding Protein; C494918:AKT1 protein, human