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A novel tumor suppressor network in squamous malignancies

Clotilde Costa1, Mirentxu Santos, Carmen Segrelles

  • 1Molecular Oncology Unit, Department of Basic Research, CIEMAT (Ed 70A), Ave Complutense 40. 28040 Madrid, Spain.

Scientific Reports
|November 13, 2012
PubMed

Insights

The retinoblastoma (Rb) protein and its relative p107 act as tumor suppressors in stratified epithelia. Their combined loss impairs p53 function, leading to squamous carcinoma development, a process partially inhibited by mTOR blockers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The retinoblastoma gene (Rb1) ablation in stratified epithelia increases proliferation but doesn't cause tumors.
  • The pRb relative, p107, compensates for pRb loss, but combined deficiency (Rb(F/F);K14cre;p107(-/-)) is lethal postnatally.

Purpose of the Study:

  • To investigate the specific tumor suppressor functions of p107 in stratified epithelia lacking pRb.
  • To establish a new mouse model for squamous cell carcinoma.

Main Methods:

  • Utilized an inducible mouse model (Rb(F/F);K14creER(TM)) for controlled gene ablation.
  • Analyzed the impact of simultaneous pRb and p107 loss on p53 function, Pten expression, and tumor development.
  • Assessed the efficacy of mTOR inhibition in tumor suppression.

Main Results:

  • Simultaneous loss of pRb and p107 in stratified epithelia leads to impaired p53 transcriptional activity and reduced Pten levels.
  • This genetic combination enables spontaneous squamous carcinoma development in mice.
  • The generated tumors exhibit significant similarities to human squamous carcinomas.
  • mTOR inhibition partially alleviated tumor development in vivo.

Conclusions:

  • p107 has distinct tumor suppressor functions in stratified epithelia when pRb is absent.
  • A novel functional link between pRb, p107, Pten, and p53 tumor suppressors in squamous tumor development is identified.
  • The Rb(F/F);K14creER(TM);p107(-/-) mouse model is valuable for studying squamous malignancies.
  • Targeting mTOR may offer therapeutic potential for related cancers.

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