Tuberous sclerosis complex 1

An epithelial tumor suppressor essential to prevent spontaneous prostate cancer in aged mice

Raleigh D. Kladney, Robert Cardiff, David J. Kwiatkowski, Gary G. Chiang, Jason D. Weber, Jeffrey M. Arbeit, Zhi Hong Lu

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The phosphoinositide 3-kinase (PI3K) pathway regulates mammalian cell growth, survival, and motility and plays a major pathogenetic role in human prostate cancer (PCa). However, the oncogenic contributions downstream of the PI3K pathway made by mammalian target of rapamycin complex 1 (mTORC1)-mediated cell growth signal transduction in PCa have yet to be elucidated in detail. Here, we engineered constitutive mTORC1 activation in prostate epithelium by a conditional genetic deletion of tuberous sclerosis complex 1 (Tsc1), a potent negative regulator of mTORC1 signaling. Epithelial inactivation was not immediately tumorigenic, but Tsc1-deficient mice developed prostatic intraepithelial neoplasia (mPIN) in lateral and anterior prostates by 6 months of age, with increasing disease penetrance over time. Lateral prostate lesions in 16- to 22-month-old mutant mice progressed to two types of more advanced lesions, adenomatous gland forming lesion (Type 1) and atypical glands embedded in massively expanded reactive stroma (Type 2). Both Type 1 and Type 2 lesions contained multiple foci of microinvasive carcinoma. Epithelial neoplastic and atypical stromal lesions persisted despite 4 weeks of RAD001 chemotherapy. Rapalogue resistance was not due to AKT or extracellular signal-regulated kinase 1/2 activation. Expression of the homeobox gene Nkx3.1 was lost in Tsc1-deficient mPIN, and it cooperated with TSC1 loss in mPIN initiation in doubly mutant Tsc1:Nkx3.1 prostatic epithelial knockout mice. Thus, TSC1 inactivation distal to PI3K and AKT activation is sufficient to activate a molecular signaling cascade producing prostatic neoplasia and focal carcinogenesis.

Original languageEnglish (US)
Pages (from-to)8937-8947
Number of pages11
JournalCancer Research
Volume70
Issue number21
DOIs
StatePublished - Nov 1 2010

Fingerprint

Tuberous Sclerosis
Prostatic Intraepithelial Neoplasia
1-Phosphatidylinositol 4-Kinase
Prostatic Neoplasms
Prostate
Neoplasms
Mitogen-Activated Protein Kinase 3
Penetrance
Homeobox Genes
Mitogen-Activated Protein Kinase 1
Growth
Knockout Mice
Cell Movement
Signal Transduction
Cell Survival
Carcinogenesis
Epithelium
Carcinoma
Drug Therapy
Tuberous Sclerosis 1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Tuberous sclerosis complex 1 : An epithelial tumor suppressor essential to prevent spontaneous prostate cancer in aged mice. / Kladney, Raleigh D.; Cardiff, Robert; Kwiatkowski, David J.; Chiang, Gary G.; Weber, Jason D.; Arbeit, Jeffrey M.; Lu, Zhi Hong.

In: Cancer Research, Vol. 70, No. 21, 01.11.2010, p. 8937-8947.

Research output: Contribution to journalArticle

Kladney, Raleigh D. ; Cardiff, Robert ; Kwiatkowski, David J. ; Chiang, Gary G. ; Weber, Jason D. ; Arbeit, Jeffrey M. ; Lu, Zhi Hong. / Tuberous sclerosis complex 1 : An epithelial tumor suppressor essential to prevent spontaneous prostate cancer in aged mice. In: Cancer Research. 2010 ; Vol. 70, No. 21. pp. 8937-8947.
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