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PP1, PKA and DARPP-32 in breast cancer: A retrospective assessment of protein and mRNA expression
Behnaz Saidy1, Shreeya Kotecha1, Anna Butler1
1Division of Cancer and Stem Cells, Nottingham Breast Cancer Research Centre, School of Medicine, University of Nottingham Biodiscovery Institute, Nottingham, UK.
Abstract:
Cyclic AMP-dependent protein kinase A (PKA) and protein phosphatase 1 (PP1) are proteins involved in numerous essential signalling pathways that modulate physiological and pathological functions. Both PP1 and PKA can be inhibited by dopamine- and cAMP-regulated phosphoprotein 32 kD (DARPP-32). Using immunohistochemistry, PKA and PP1 expression was determined in a large primary breast tumour cohort to evaluate associations between clinical outcome and clinicopathological criteria (n > 1100). In addition, mRNA expression of PKA and PP1 subunits was assessed in the METABRIC data set (n = 1980). Low protein expression of PKA was significantly associated with adverse survival of breast cancer patients; interestingly, this relationship was stronger in ER-positive breast cancer patients. PP1 protein expression was not associated with patient survival. PKA and PP1 subunit mRNA was also assessed; PPP1CA, PRKACG and PRKAR1B were associated with breast cancer-specific survival. In patients with high expression of DARPP-32, low expression of PP1 was associated with adverse survival when compared to high expression in the same group. PKA expression and PP1 expression are of significant interest in cancer as they are involved in a wide array of cellular processes, and these data indicate PKA and PP1 may play an important role in patient outcome.
Insights
Low cyclic AMP-dependent protein kinase A (PKA) expression correlates with poorer breast cancer survival, particularly in ER-positive cases. Protein phosphatase 1 (PP1) roles are complex and context-dependent.
Area of Science:
- Molecular biology
- Cancer research
- Biochemistry
Background:
- Cyclic AMP-dependent protein kinase A (PKA) and protein phosphatase 1 (PP1) are key regulators of cellular signaling.
- Dopamine- and cAMP-regulated phosphoprotein 32 kDa (DARPP-32) inhibits both PKA and PP1.
- Dysregulation of these proteins is implicated in various physiological and pathological conditions, including cancer.
Purpose of the Study:
- To investigate the association between PKA and PP1 expression and clinical outcomes in breast cancer patients.
- To evaluate the relationship between PKA and PP1 protein and mRNA levels and patient survival.
- To explore the role of DARPP-32 in modulating the prognostic significance of PKA and PP1.
Main Methods:
- Immunohistochemistry was used to assess PKA and PP1 protein expression in a large cohort of primary breast tumors (n > 1100).
- mRNA expression of PKA and PP1 subunits was analyzed in the METABRIC dataset (n = 1980).
- Statistical analyses were performed to correlate protein and mRNA expression with patient survival and clinicopathological features.
Main Results:
- Low PKA protein expression was significantly associated with adverse breast cancer patient survival, especially in ER-positive tumors.
- PP1 protein expression did not show a significant association with patient survival.
- Specific PKA and PP1 subunit mRNAs (PPP1CA, PRKACG, PRKAR1B) were linked to breast cancer-specific survival.
- In patients with high DARPP-32, low PP1 expression correlated with worse survival.
Conclusions:
- PKA protein expression is a significant prognostic marker for breast cancer survival, particularly in ER-positive subtypes.
- The prognostic role of PP1 in breast cancer appears context-dependent, influenced by factors like DARPP-32 levels.
- These findings highlight the potential importance of PKA and PP1 in breast cancer progression and patient outcomes.
