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PTEN ablation in Ras(Ha)/Fos skin carcinogenesis invokes p53-dependent p21 to delay conversion while p53-independent

F H Macdonald1, D Yao1, J A Quinn1

  • 1Dermatology Section, School of Medicine, Dentistry and Nursing, College of Medical, Veterinary and Life Sciences, Glasgow University, Glasgow, UK.

Oncogene
|September 17, 2013
PubMed

Insights

Loss of PTEN in mouse skin cancer models accelerates tumor growth but delays malignant conversion by inducing p53 and p21. Persistent p21 limits progression, while its loss drives aggressive carcinomas.

Area of Science:

  • Oncology
  • Molecular Biology
  • Dermatology

Background:

  • Understanding oncogenic pathways is crucial for cancer progression research.
  • PTEN loss is implicated in various cancers, but its role in skin carcinogenesis with specific oncogenes needs clarification.

Purpose of the Study:

  • To investigate the role of inducible PTEN ablation in skin carcinogenesis driven by ras(Ha)/fos oncogenes.
  • To elucidate the mechanisms of tumor progression, differentiation, and malignant conversion in response to oncogenic insults.

Main Methods:

  • Utilized transgenic mouse models with inducible PTEN ablation (Δ5PTEN(flx)) and activated ras(Ha)/fos oncogenes.
  • Administered RU486 to induce PTEN ablation and TPA for promotion in specific cohorts.
  • Analyzed keratinocyte proliferation, hyperplasia, cyst formation, papillomatogenesis, and tumor histotypes (wdSCC, pdSCC).
  • Assessed expression levels of p53, p21, cyclin D1, and cyclin E2 using western and immunofluorescence techniques.

Main Results:

  • Inducible PTEN ablation in HK1.ras/fos mice accelerated papillomatogenesis but delayed malignant conversion, yielding well-differentiated squamous cell carcinomas (wdSCC).
  • Early epidermal responses involved p53/p21 induction, altering differentiation and diverting proliferation into cysts.
  • Malignant conversion required p53 loss; persistent p53-independent p21 expression limited progression in wdSCCs by inhibiting cyclins D1/E2.
  • Conversely, TPA-promoted HK1.ras-Δ5PTEN(flx) mice lost p53/p21 early, rapidly forming poorly differentiated carcinomas (pdSCCs) with cell-cycle control failures.

Conclusions:

  • PTEN loss cooperates with ras(Ha)/fos to induce p53/p21, initially limiting malignant progression in skin carcinogenesis.
  • p53 loss is essential for malignant conversion, but sustained p21 expression acts as a barrier to early-stage progression.
  • Differential regulation of cell-cycle proteins (cyclins D1/E2) by p21 influences tumor differentiation and aggressiveness.

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