Activation of an actin signaling pathway in pre-malignant mammary epithelial cells by P-cadherin is essential for transformation

• Published in: Disease models & mechanisms Vol. 16; no. 2
• Main Authors: Faria, Lídia, Canato, Sara, Jesus, Tito T, Gonçalves, Margarida, Guerreiro, Patrícia S, Lopes, Carla S, Meireles, Isabel, Morais-de-Sá, Eurico, Paredes, Joana, Janody, Florence
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 01-02-2023; The Company of Biologists
• Subjects: Actin; actin cytoskeleton; Actins - metabolism; Breast; Breast cancer; Breast carcinoma; Cadherins; Carcinogenesis; Cell activation; Cell adhesion & migration; Cell adhesion molecules; Cell division; Cell migration; Cell self-renewal; Cytoskeleton; drosophila; Epithelial cells; Epithelial Cells - metabolism; Genes; human mammary epithelial cells; Humans; Insects; Kinases; Localization; Mammary gland; mrtf-a–srf signaling; Nuclear transport; p-cadherin; Phenotypes; Polymerization; pre-malignant lesions; Serum Response Factor - genetics; Serum Response Factor - metabolism; Signal Transduction; Trans-Activators - metabolism; Human mammary epithelial cells; P-cadherin; MRTF-A–SRF signaling; Actin cytoskeleton; Pre-malignant lesions; Drosophila
• ISSN: 1754-8403; 1754-8411
• DOI: 10.1242/dmm.049652

Alterations in the expression or function of cell adhesion molecules have been implicated in all steps of tumor progression. Among those, P-cadherin is highly enriched in basal-like breast carcinomas, playing a central role in cancer cell self-renewal, collective cell migration and invasion. To establish a clinically relevant platform for functional exploration of P-cadherin effectors in vivo, we generated a humanized P-cadherin Drosophila model. We report that actin nucleators, Mrtf and Srf, are main P-cadherin effectors in fly. We validated these findings in a human mammary epithelial cell line with conditional activation of the SRC oncogene. We show that, prior to promoting malignant phenotypes, SRC induces a transient increase in P-cadherin expression, which correlates with MRTF-A accumulation, its nuclear translocation and the upregulation of SRF target genes. Moreover, knocking down P-cadherin, or preventing F-actin polymerization, impairs SRF transcriptional activity. Furthermore, blocking MRTF-A nuclear translocation hampers proliferation, self-renewal and invasion. Thus, in addition to sustaining malignant phenotypes, P-cadherin can also play a major role in the early stages of breast carcinogenesis by promoting a transient boost of MRTF-A-SRF signaling through actin regulation.