Recurrent PPP2R1A Mutations in Uterine Cancer Act through a Dominant Negative Mechanism to Promote Malignant Cell Growth.
Somatic missense mutations in the Ser/Thr protein phosphatase 2A (PP2A) Aa scaffold subunit gene PPP2R1A are among the few genomic alterations that occur frequently in serous endometrial carcinoma (EC) and carcinosarcoma, two clinically aggressive subtypes of uterine cancer with few therapeutic options. Previous studies reported that cancer associated Aa mutants exhibit defects in binding to other PP2A subunits and contribute to cancer development by a mechanism of haploinsufficiency. Here we report on the functional significance of the most recurrent PPP2R1A mutations in human EC, which cluster in Aa HEAT repeats 5 and 7. Beyond predicted loss of function effects on the formation of a subset of PP2A holoenzymes, we discovered that Aa mutants behave in a dominant negative manner due to gain of function interactions with the PP2A inhibitor TIPRL1. Dominant negative Aa mutants retain binding to specific subunits of the B56/B' family and form substrate trapping complexes with impaired phosphatase activity via increased recruitment of TIPRL1. Accordingly, overexpression of the Aa mutants in EC cells harboring wild type PPP2R1A increased anchorage independent growth and tumor formation, and triggered hyperphosphorylation of oncogenic PP2A B56/B' substrates in the GSK3b, Akt, and mTOR/p70S6K signaling pathways. TIPRL1 silencing restored GSK3b phosphorylation and rescued the EC cell growth advantage. Our results reveal how PPP2R1A mutations affect PP2A function and oncogenic signaling, illuminating the genetic basis for serous EC development and its potential control by rationally targeted therapies. Cancer Res; 76(19) 5719 31. (c)2016 AACR.
Cancer research