Physiological levels of Pik3ca(H1047R) mutation in the mouse mammary gland results in ductal hyperplasia and formation of ERα-positive tumors.
PIK3CA, the gene coding for the p110α subunit of phosphoinositide 3-kinase, is frequently mutated in a variety of human tumors including breast cancers. To better understand the role of mutant PIK3CA in the initiation and/or progression of breast cancer, we have generated mice with a conditional knock-in of the common activating mutation, Pik3ca(H1047R), into one allele of the endogenous gene in the mammary gland. These mice developed a ductal anaplasia and hyperplasia by 6 weeks of age characterized by multi-layering of the epithelial lining of the mammary ducts and expansion of the luminal progenitor (Lin(-); CD29(lo); CD24(+); CD61(+)) cell population. The Pik3ca(H1047R) expressing mice eventually develop mammary tumors with 100% penetrance but with a long latency (>12 months). This is significantly longer than has been reported for transgenic models where expression of the mutant Pik3ca is driven by an exogenous promoter. Histological analysis of the tumors formed revealed predominantly ERα-positive fibroadenomas, carcinosarcomas and sarcomas. In vitro induction of Pik3ca(H1047R) in immortalized mammary epithelial cells also resulted in tumor formation when injected into the mammary fat pad of immunodeficient recipient mice. This novel model, which reproduces the scenario of a heterozygous somatic mutation occurring in the endogenous PIK3CA gene, will thus be a valuable tool for investigating the role of Pik3ca(H1047R) mutation in mammary tumorigenesis both in vivo and in vitro.
Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Anjali
A
Tikoo
Vincent
V
Roh
Karen G
KG
Montgomery
Ivan
I
Ivetac
Paul
P
Waring
Rebecca
R
Pelzer
Lauren
L
Hare
Mark
M
Shackleton
Patrick
P
Humbert
Wayne A
WA
Phillips
D000483:Alleles; D000818:Animals; D001483:Base Sequence; D058534:Class I Phosphatidylinositol 3-Kinases; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D055879:Gene Knock-In Techniques; D006965:Hyperplasia / Q000201:enzymology / Q000235:genetics; D008321:Mammary Glands, Animal / Q000201:enzymology* / Q000254:growth & development / Q000473:pathology*; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics
D058534:Class I Phosphatidylinositol 3-Kinases; D047628:Estrogen Receptor alpha; D019869:Phosphatidylinositol 3-Kinases; C546639:Pik3ca protein, mouse