Investigating The Role Of Mesenchymal Cell-Mediated Paracrine Signaling In Breast Cancer Cell Proliferation And Invasion In A Heterotypic 3D Co-culture Model

Breast cancer (BC) is a complex heterogenous and fatal disease. Increased expression of proliferation marker, Ki-67 and mesenchymal-like phenotype resulting from the epithelial-mesenchymal transformation (EMT) highlight transformation of in situ ductal carcinoma (DCIS) into invasive breast cancer (IBC) associates with poor prognosis in patients. Previous indirect 2D co-culture studies have demonstrated that mesenchymal stem cells (MSCs) promote BC progression through secretion of paracrine factors including growth factors, cytokines and chemokines. In order to investigate this aspect of the tumour microenvironment in a more relevant 3D co-culture model, spheroids incorporating breast cancer cells (BCCs), both cell lines and primary BCCs expanded as patient-derived xenografts, and MSCs were established. MSCs in co-cultures were shown to enhance proliferation in BCCs and altered the native cytoskeletal arrangement of actin filament in estrogen receptor (ER)/progesterone (PR) receptor-positive BCCs. In addition, co-culture resulted in downregulation of E-cadherin in parallel with upregulation of the EMT-relation transcription factor, SNAIL. Cytoplasmic relocalization of SnON, a negative regulator of TGF-β signalling, and of β-catenin, involved in Wnt signalling, was also observed in BCCs in co-cultures in contrast to monocultures. In addition, the β-catenin inhibitor, 3â?[[(4â?methylphenyl)sulfonyl]amino]â?benzoic acid methyl ester (MSAB), mediated reduced growth and invasion in the co-cultures. This study highlights the potential role for SnON as a bio-marker for BC invasiveness, and the importance of interactions between TGF-β and Wnt signalling, involving SnON. Such pathways may contribute towards identifying possible targets for therapeutic intervention in BC patients.

Author(s): Amarnath Pal

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