Genetic analysis of Pten and Tsc2 functional interactions in the mouse reveals asymmetrical haploinsufficiency in tumor suppression (original) (raw)

  1. Li Ma1,2,3,
  2. Julie Teruya-Feldstein2,6,
  3. Nille Behrendt2,6,
  4. Zhenbang Chen1,2,
  5. Tetsuo Noda4,
  6. Okio Hino5,
  7. Carlos Cordon-Cardo2, and
  8. Pier Paolo Pandolfi1,2,7
  9. 1Cancer Biology and Genetics Program, 2Department of Pathology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA;3Graduate Program in Physiology, Biophysics and Systems Biology, Weill Graduate School of Medical Sciences, Cornell University, New York, New York 10021, USA; 4Department of Cell Biology and 5Department of Experimental Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 170-8455, Japan

Abstract

The role of tumor suppressor haploinsufficiency in oncogenesis is still poorly understood. The PTEN and TSC2 tumor suppressors function to antagonize mTOR (mammalian target of rapamycin) activation by Akt; hence, compound heterozygous inactivation of_Pten_ and Tsc2 in the mouse may in principle exacerbate the tumor phenotypes observed in the single mutants in a reciprocal manner. In contrast, we found that while Tsc2 heterozygosity unmasks Pten haploinsufficiency in growth and tumor suppression, tumorigenesis in Tsc2+/- mutants is surprisingly not accelerated by Pten heterozygosity, even though mTOR activation is cooperatively enhanced by compound Pten/Tsc2 heterozygosity. We show that the wild-type alleles of both Pten and Tsc2 are retained in prostate tumors from both Pten+/- and Pten+/-Tsc2+/- mice, whereas TSC-related tumor lesions are invariably associated with Tsc2 loss of heterozygosity (LOH) in both Tsc2+/- and Pten+/-Tsc2+/- mice. These findings demonstrate that inactivation of TSC2 is epistatic to PTEN in the control of tumor initiation and progression and, importantly, that both Pten and Tsc2 are haploinsufficient for suppression of tumorigenesis initiated by Pten heterozygosity, while neither Pten nor Tsc2 is haploinsufficient for repression of carcinogenesis arising from Tsc2 heterozygosity, providing a rationale for the differential cancer susceptibility of the two human conditions associated with_PTEN_ or TSC2 heterozygous mutations.

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