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The potential role of the hedgehog signalling pathway in the regulation of epithelial-mesenchymal transition in breast cancer

Flemban, Arwa


Arwa Flemban


Breast cancer is a deadly disease that accounts for a third of all female cancer- related deaths globally. Although recent advances in early diagnosis and targeted therapy using prognostic markers have reduced deaths, more than 50% of newly diagnosed cases have already developed metastatic disease at diagnosis. Furthermore, the remaining cases still have a high risk of secondary disease and relapse. Breast cancer metastasis is the leading cause of breast cancer related mortality, it is incurable and current treatments aims to prolong life alongside pain management. Thus, there is a need for treatment for this disease.
The epithelial-mesenchymal transition (EMT) is the process by which cancer cells acquire the ability to invade and eventually metastasise. Therefore, understanding the regulation of breast cancer cell metastasis is essential for identifying methods for management of metastatic disease either by prevention or treatment. The first aim of this study was to confirm the ability of breast cancer cell lines, that belong to several molecular subtypes to undergo EMT using an in vitro seeding density model. Results showed that there was active EMT in breast cancer cell lines and that the activation of these pathways is not restricted to, nor governed by, molecular subtypes of breast cancer. Then to identify pathways involved in regulating EMT and utilising these pathways as prognostic marker as well as for developing treatments.
The Hedgehog (Hh) signalling pathway is involved in the regulation of EMT during mammary gland development stages. This pathway was involved in the progression and metastasis of many human cancers. So, the expression of a number of proteins involved in the Hh pathway were assessed in a cohort of breast cancer patient samples. The expression of these proteins in the tumour centre and also the invasive front was assessed and correlated with the clinicopathological criteria. Data from breast cancer cohort showed that there was increased expression of Hh proteins (Gli1, Gli2 and Gli3) at the invasive front. Also, the data suggested that breast cancer cells gain the ability to activate Hh signalling by autocrine rather than by paracrine signalling. These findings encouraged further investigation to understand the effect of inhibiting the Hh signalling using cyclopamine or LDE225 in vitro.
Inhibition with cyclopamine or LDE225 resulted in a reduction of cell yield and viability that correlated with increased cellular apoptosis. The reduction in viability and increased cell death was associated with alteration of Hh proteins expression and subcellular localisation. Also, assessment of the catenin-related transcription, that measured the outputs of canonical Wnt signalling, showed that inhibiting Hh signalling using cyclopamine and LDE225 resulted in reduction of Wnt signalling activity in both cell lines. Assessment of E-cadherin expression showed that Hh inhibition caused increased of expression in both cell lines, that was associated with a reduction of cells invasion.
Findings showed that Hh signalling was involved in the regulation of EMT and that there was crosstalk between Hh and Wnt signalling in breast cancer cells. It can be concluded that the combined activation of Hh and Wnt signalling in breast cancer was associated with increased metastasis as a result of EMT activation. Assessment of the co-expression of Hh and Wnt signalling proteins in breast cancer samples provides potential prognostic markers for identifying breast cancer patients who that could benefit from Hh-targeted therapy.


Flemban, A. (2019). The potential role of the hedgehog signalling pathway in the regulation of epithelial-mesenchymal transition in breast cancer. (Thesis). University of the West of England. Retrieved from

Thesis Type Thesis
Deposit Date Apr 5, 2019
Publicly Available Date Apr 6, 2020
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