PEAK1 Acts as a Molecular Switch to Regulate Context-Dependent TGFβ Responses in Breast Cancer

Most Common Cancer – Breast Cancer with 24% Survival Rate

Around 23% of all cancer cases are of breast cancer which is the most common cancer among woman and those with metastatic type of this condition tend to have 24% survival rate. Comprehending the molecular regulation of the metastatic flow as well as the development of metastatic tumours could enlighten the strategies in helping in the chances of survival of the patient.

In the framework of human cancers, transforming growth factor beta – TGFB, could act as a tumour suppressor or a pro-tumorigenic factor which would be capable of inducing epithelial to mesenchymal transition – EMTas well as metastasis. EMT is a morphologic and phenotypic change in the cells which tends to get associated with precise deviationsin gene expression. It is necessary and severely regulated during embryogenesis as well as tissue homeostasis.

However, it is decontrolled during the development of epithelial cancers to promote metastasis. At the time of EMT, the cells slowly tend to lose their apical basal polarity, the potential to attach to the basement membrane and protein complexes which tend to control cell-cell junctions. These changes are also related with down-regulation of epithelial genes with greater than before expression of mesenchymal genes. The outcome of which is that cells tend to migrate more extensively and accept a more spread fibroblast like morphology.

TGFB Signalling Mechanisms to be Changed

TGFB exposure, as a tumour suppressor, promotes cytostasis, apoposis and differentiation and acts to stimulate an appropriate immune response. But the TGFB’s signalling mechanisms could be changed to impede its anti-proliferative effects and stimulate tumorigenic effects. Environmental signals and cell type are factors which can determine if TGFB acts in tumour suppressive or tumour promoting and it is learnt how the signalling pathways tend to become modified; a thorough understanding of the molecular regulation which tends to drive this change in TGFB responses is yet to be fully interpreted.

With regards to TGFB and ECM growth element pathways have been portrayed to cooperate in promoting EMT, migration, invasion as well as metastasis of breast cancer cells.Earlier reports had verified that specific extracellular matrix proteins could cooperate with TGFB receptors to change TGFB sins from its canonical Smad2/3 pathway to non-canonical Src/RBRII/Grb2/MAPK indicating pathways. This change has been described to be a key mechanism from which TGFB accepts its pro-tumorigenic tasks

PEAK1 Expression in Breast Cancer Samples Analysed

In the present study, pseudopodium enriched atypical kinase 1 - PEAK1 expression in human breast cancer samples were analysed and it was found that PEAK1 levels associate with mesenchymal gene expression, disease relapse and poor cellular differentiation. It was observed at the cellular level that PEAK1 expression was the highest in mesenchymal breast cancer cells, linked with migration capabilities and increased in response to TGFB induced epithelial mesenchymal transition.

Hence, the need to evaluate the role of PEAK1 in the changing of TGFB from a tumour supressing to tumour promoting factor came up. It was discovered that high PEAK1 expression resulted in TGFB losing its anti-proliferative effects potentiates TGFB induced proliferation, EMT, cell migration and tumour metastasis in fibronectin-dependent manner. PEAK1 also resulted in changing of TGFB signs from its canonical Smad2/3 pathway to non-canonical Src and MAPK signs.

This is the first report in providing evidence that PEAK1 arbitrates signalling cross talk between TGFB receptors and integrin/Src/MAPK pathways. PEAK1 is also an important molecular regulator of TGFB induced tumour progression as well as metastasis in breast cancer.