Loss of p21WAF1/CIP1 accelerates Ras oncogenesis in a transgenic/knockout mammary cancer model

Oncogene. 2000 Nov 9;19(47):5338-47. doi: 10.1038/sj.onc.1203956.


Upregulation of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 and subsequent cell growth arrest or senescence is one mechanism by which normal cells are believed to respond to stress induced by the constitutively activated GTPase Ras. We hypothesize that in the absence of p21, the onset of Ras-dependent oncogenesis is accelerated. To test this hypothesis, we crossed MMTV/v-Ha-ras transgenic mice into a p21-deficient background. By 63 days of age, all 8 ras/p21-/- mice developed either malignant (mammary and/or salivary adenocarcinomas) or benign (Harderian hyperplasia) tumors. In contrast, by the same age, only one out of nine of the ras/p21+/+ mice developed a tumor. Furthermore, by 94 days of age, half of the ras/p21-/- mice, but none of the ras/p21+/+ mice, developed mammary tumors. p21-deficiency also accelerated the development of salivary (T50=66 days for ras/p21-/- vs T50=136 days for ras/p21+/+) and Harderian (T50=52 days for ras/p21-/- vs T50>221 days for ras/p21+/+) tumors. Furthermore, two out of the eight ras/p21-/- mice had metastatic lesions, one in its lungs, the other in its abdomen. None of the nine ras/p21+/+ mice had metastatic lesions. By 4 months of age, the mammary tumor multiplicity was 10-fold greater in ras/p21-/- (average 3.40 tumors/mouse) than in ras/p21+/+ (average 0.33 tumor/mouse) mice. However, once the tumors appeared, their growth rate, apoptosis level, and mitotic index were not affected by the loss of p21, suggesting that loss of p21 is critical in early but not late events of Ras oncogenesis. Altogether, the results show that tumor onset in MMTV/v-Ha-ras mice is p21-dependent with loss of p21 associated with earlier tumor appearance and increased tumor multiplicity and aggressiveness.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenocarcinoma / etiology
  • Adenocarcinoma / genetics
  • Adenocarcinoma / pathology
  • Adenocarcinoma / physiopathology
  • Animals
  • Carcinoma, Ductal, Breast / etiology
  • Carcinoma, Ductal, Breast / genetics
  • Carcinoma, Ductal, Breast / pathology
  • Carcinoma, Ductal, Breast / physiopathology*
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / genetics
  • Cyclins / physiology*
  • Disease Models, Animal
  • Female
  • Gene Expression
  • Genes, ras / physiology*
  • Male
  • Mammary Neoplasms, Animal / etiology
  • Mammary Neoplasms, Animal / genetics
  • Mammary Neoplasms, Animal / pathology
  • Mammary Neoplasms, Animal / physiopathology*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Oncogene Protein p21(ras) / genetics
  • Oncogene Protein p21(ras) / physiology*
  • Salivary Gland Neoplasms / etiology
  • Salivary Gland Neoplasms / genetics
  • Salivary Gland Neoplasms / pathology
  • Salivary Gland Neoplasms / physiopathology


  • Cdkn1a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Oncogene Protein p21(ras)