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The prognostic significance and value of cyclin D1, CDK4 and p16 in human breast cancer.

Peurala E, Koivunen P, Haapasaari KM, Bloigu R, Jukkola-Vuorinen A - Breast Cancer Res. (2013)

Bottom Line: 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.In conclusion, it appears that cyclin D1, CDK4 and p16 function independently in human breast cancer.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: 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. 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.

Methods: The 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.

Results: High 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.

Conclusions: Cyclin 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.

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Regulation of the cell cycle G1/S transition by cyclin D1, CDK4 and p16. RB, retinoblastoma protein, CDK4/6, cyclin-dependent kinase 4/6.
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Figure 1: Regulation of the cell cycle G1/S transition by cyclin D1, CDK4 and p16. RB, retinoblastoma protein, CDK4/6, cyclin-dependent kinase 4/6.

Mentions: The retinoblastoma tumor suppressor gene (RB) encodes a nuclear phosphoprotein that plays a central role in regulating the cell cycle [1]. RB regulates progression through the G1-to-S phase transition of the cell cycle [1]. Loss of RB is well documented in many human tumor types and it is probable that the p16-cyclin D1-CDK4/6-RB pathway is disrupted in most human malignancies [2]. Extracellular signals induce the expression of cyclin D1 in cells entering the cell cycle and this binds to and activates cyclin-dependent kinases (CDK4 and CDK6) (Figure 1) [1-5]. The ensuing complexes in turn lead to the phosphorylation of RB, resulting in its dissociation from the transcription factors, predominantly members of the E2F family, which then activate the many genes required for progression of the cell cycle to the S phase (Figure 1) [1-3]. p16, also known as p16INK4a, a member of the INK4 family of CDK inhibitors, inhibits CDK4 and CDK6, maintaining RB in its hypophosphorylated E2F-associated state, and thereby preventing G1-to-S phase progression (Figure 1) [6,7]. Inactivation of p16 results in a loss of the inhibition of RB phosphorylation, facilitating a loss of control over cell cycle arrest [2]. In the case of breast tumors there may be genetic events upstream of RB which can negatively affect RB function by promoting its phosphorylation. These may include p16 loss [5] and CCND1 amplification or Cyclin D1 overexpression [8].


The prognostic significance and value of cyclin D1, CDK4 and p16 in human breast cancer.

Peurala E, Koivunen P, Haapasaari KM, Bloigu R, Jukkola-Vuorinen A - Breast Cancer Res. (2013)

Regulation of the cell cycle G1/S transition by cyclin D1, CDK4 and p16. RB, retinoblastoma protein, CDK4/6, cyclin-dependent kinase 4/6.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3672746&req=5

Figure 1: Regulation of the cell cycle G1/S transition by cyclin D1, CDK4 and p16. RB, retinoblastoma protein, CDK4/6, cyclin-dependent kinase 4/6.
Mentions: The retinoblastoma tumor suppressor gene (RB) encodes a nuclear phosphoprotein that plays a central role in regulating the cell cycle [1]. RB regulates progression through the G1-to-S phase transition of the cell cycle [1]. Loss of RB is well documented in many human tumor types and it is probable that the p16-cyclin D1-CDK4/6-RB pathway is disrupted in most human malignancies [2]. Extracellular signals induce the expression of cyclin D1 in cells entering the cell cycle and this binds to and activates cyclin-dependent kinases (CDK4 and CDK6) (Figure 1) [1-5]. The ensuing complexes in turn lead to the phosphorylation of RB, resulting in its dissociation from the transcription factors, predominantly members of the E2F family, which then activate the many genes required for progression of the cell cycle to the S phase (Figure 1) [1-3]. p16, also known as p16INK4a, a member of the INK4 family of CDK inhibitors, inhibits CDK4 and CDK6, maintaining RB in its hypophosphorylated E2F-associated state, and thereby preventing G1-to-S phase progression (Figure 1) [6,7]. Inactivation of p16 results in a loss of the inhibition of RB phosphorylation, facilitating a loss of control over cell cycle arrest [2]. In the case of breast tumors there may be genetic events upstream of RB which can negatively affect RB function by promoting its phosphorylation. These may include p16 loss [5] and CCND1 amplification or Cyclin D1 overexpression [8].

Bottom Line: 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.In conclusion, it appears that cyclin D1, CDK4 and p16 function independently in human breast cancer.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: 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. 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.

Methods: The 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.

Results: High 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.

Conclusions: Cyclin 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.

Show MeSH
Related in: MedlinePlus