The p110α and p110β isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis.
Class Ia phosphatidylinositol 3 kinase (PI3K) is required for oncogenic receptor-mediated transformation; however, the individual roles of the two commonly expressed class Ia PI3K isoforms in oncogenic receptor signaling have not been elucidated in vivo. Here, we show that genetic ablation of p110α blocks tumor formation in both polyoma middle T antigen (MT) and HER2/Neu transgenic models of breast cancer. Surprisingly, p110β ablation results in both increased ductal branching and tumorigenesis. Biochemical analyses suggest a competition model in which the less active p110β competes with the more active p110α for receptor binding sites, thereby modulating the level of PI3K activity associated with activated receptors. Our findings demonstrate a novel p110β-based regulatory role in receptor-mediated PI3K activity and identify p110α as an important target for treatment of HER2-positive disease.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Tamara
T
Utermark
Trisha
T
Rao
Hailing
H
Cheng
Qi
Q
Wang
Sang Hyun
SH
Lee
Zhigang C
ZC
Wang
J Dirk
JD
Iglehart
Thomas M
TM
Roberts
William J
WJ
Muller
Jean J
JJ
Zhao
D000818:Animals; D000957:Antigens, Viral, Tumor / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D008321:Mammary Glands, Animal / Q000201:enzymology* / Q000254:growth & development / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011120:Polyomavirus / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism
D000957:Antigens, Viral, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; C524056:Erbb2 protein, mouse