Abstract
IntroductionLoss of the retinoblastoma protein tumor suppressor gene (RB) coding for a nuclear phosphoprotein that regulates the cell cycle is found in many human cancers and probably leads to disruption of the p16-cyclin D1-CDK4/6-RB pathway. Cyclin D1 is known to activate CDK4, which then phosphorylates the RB protein, leading to cell cycle progression. p16 inhibits CDK4, keeping RB hypophosphorylated and preventing cell cycle progression. The significance of these three markers, cyclin D1, CDK4 and p16, for breast cancer and carcinogenesis is nevertheless still controversial.MethodsThe material consisted of 102 formalin-fixed human breast cancer samples, in which cyclin D1, CDK4 and p16 expression was evaluated immunohistochemically. The amounts of cyclin D1 mRNA present were analyzed by quantitative real time PCR.ResultsHigh cyclin D1 expression statistically significantly correlated with lower tumor grade, estrogen and progesterone receptor positivity and lower proliferation activity in breast tumors and increased breast cancer-specific survival and overall survival. Tumors with high cyclin D1 protein had 1.8 times higher expression of cyclin D1 mRNA. CDK4 expression did not correlate with cyclin D1 expression or the survival data. p16 expression was associated with Human Epidermal Growth Factor Receptor 2 (HER2) negativity and increased breast cancer-specific survival and disease-free survival. No statistical correlations between cyclin D1, CDK4 and p16 were found.ConclusionsCyclin D1 was associated with a good breast cancer prognosis but functioned independently of CDK4. High cyclin D1 expression may be partially due to increased CCND1 transcription. p16 correlated with a better prognosis and may function without CDK4. In conclusion, it appears that cyclin D1, CDK4 and p16 function independently in human breast cancer.
Highlights
Loss of the retinoblastoma protein tumor suppressor gene (RB) coding for a nuclear phosphoprotein that regulates the cell cycle is found in many human cancers and probably leads to disruption of the p16-cyclin D1-CDK4/6-retinoblastoma tumor suppressor gene (RB) pathway
Loss of RB is well documented in many human tumor types and it is probable that the p16-cyclin D1-CDK4/6RB pathway is disrupted in most human malignancies [2]
When we considered the relations between the expression of cyclin D1, CDK4 and p16 and hypoxia-inducible factor (HIF) prolyl 4-hydroxylases PHD1, 2 and 3, HIF-1a and HIF-2a, the expression of which we had studied earlier in the same samples [21], we found positive correlations between p16 and both PHD1 (P = 0.032) and PHD2
Summary
Loss of the retinoblastoma protein tumor suppressor gene (RB) coding for a nuclear phosphoprotein that regulates the cell cycle is found in many human cancers and probably leads to disruption of the p16-cyclin D1-CDK4/6-RB pathway. P16 inhibits CDK4, keeping RB hypophosphorylated and preventing cell cycle progression. Cyclin D1 is known to activate CDK4, which phosphorylates the RB protein, leading to cell cycle progression. The significance of these three markers, cyclin D1, CDK4 and p16, for breast cancer and carcinogenesis is still controversial. The retinoblastoma tumor suppressor gene (RB) encodes a nuclear phosphoprotein that plays a central role in regulating the cell cycle [1]. It has been shown that CDK4 and CDK6 are dispensable when it comes to driving the essential cell cycle, but they
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
