Naslov
Physiological Levels of Pik3ca H1047R Mutation in the Mouse Mammary Gland Results in Ductal Hyperplasia and Formation of ERa-Positive Tumors

Autori
Tikoo, Anjali ; Roh, Vincent ; Montgomery, Karen G. ; Ivetac, Ivan, Waring Paul, Pelzer, Rebecca ; Hare, Lauren ; Shackleton, Mark ; Humbert, Patrick ; Phillips, Wayne A.

Izvornik
PLoS One (1932-6203) 7 (2012), 5; 1-13

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
Estrogen Receptor alpha ; Phosphatidylinositol 3-Kinases ; PIK3CA gene ; H1047 conditional mutant ; conditional knock-in mutation ; breast neoplasm ; ductal hyperplasia ; ERα-positive tumor.
(Estrogen Receptor alpha ; Phosphatidylinositol 3-Kinases ; PIK3CA gene ; H1047 conditional mutant ; iMMECs - immortalized mouse mammary epithelial cells ; conditional knock-in mutation ; breast neoplasm ; ductal hyperplasia ; ERα-positive tumor.)

Sažetak
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, Pik3caH1047R, 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− ; CD29lo ; CD24+ ; CD61+) cell population. The Pik3caH1047R 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 Pik3caH1047R 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 Pik3caH1047R mutation in mammary tumorigenesis both in vivo and in vitro.

Izvorni jezik
Engleski

Znanstvena područja
Biologija, Interdisciplinarne prirodne znanosti, Temeljne medicinske znanosti

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