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Tuberous sclerosis complex 1: an epithelial tumor suppressor essential to prevent spontaneous prostate cancer in aged

Raleigh D Kladney1, Robert D Cardiff, David J Kwiatkowski

  • 1Division of Molecular Oncology, Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri, USA.

Cancer Research
|October 14, 2010
PubMed

Insights

Constitutive activation of mTORC1 signaling by Tsc1 deletion in prostate cells drives prostatic intraepithelial neoplasia and focal carcinogenesis, demonstrating TSC1

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • The phosphoinositide 3-kinase (PI3K) pathway is crucial for cell growth and survival, playing a significant role in prostate cancer (PCa).
  • The specific role of mammalian target of rapamycin complex 1 (mTORC1) signaling downstream of PI3K in PCa pathogenesis requires detailed investigation.

Purpose of the Study:

  • To elucidate the oncogenic contributions of mTORC1-mediated signaling in prostate cancer.
  • To investigate the effects of constitutive mTORC1 activation in prostate epithelium via Tsc1 deletion.

Main Methods:

  • Engineered constitutive mTORC1 activation in mouse prostate epithelium by conditional genetic deletion of Tsc1.
  • Analyzed lesion progression, histology, and molecular markers in Tsc1-deficient mice.
  • Investigated the role of Nkx3.1 in conjunction with Tsc1 loss.

Main Results:

  • Tsc1 deletion in prostate epithelium led to prostatic intraepithelial neoplasia (mPIN) and subsequent progression to advanced lesions with microinvasive carcinoma.
  • Lesions showed resistance to RAD001 chemotherapy, independent of AKT or ERK1/2 activation.
  • Loss of Nkx3.1 expression in Tsc1-deficient mPIN and its cooperative role with TSC1 loss in mPIN initiation were observed.

Conclusions:

  • TSC1 inactivation downstream of PI3K and AKT is sufficient to initiate a signaling cascade leading to prostatic neoplasia and carcinogenesis.
  • mTORC1 signaling plays a critical role in prostate cancer development and progression.
  • Nkx3.1 loss cooperates with TSC1 inactivation in prostate cancer initiation.

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