Loss of E-cadherin leads to Id2-dependent inhibition of cell cycle progression in metastatic lobular breast cancer

Abstract

Invasive lobular breast carcinoma (ILC) is characterized by proliferative indolence and long-term latency relapses. This study aimed to identify how disseminating ILC cells control the balance between quiescence and cell cycle re-entry. In the absence of anchorage, ILC cells undergo a sustained cell cycle arrest in G0/G1 while maintaining viability. From the genes that are upregulated in anchorage independent ILC cells, we selected Inhibitor of DNA binding 2 (Id2), a mediator of cell cycle progression. Using loss-of-function experiments, we demonstrate that Id2 is essential for anchorage independent survival (anoikis resistance) in vitro and lung colonization in mice. Importantly, we find that under anchorage independent conditions, E-cadherin loss promotes expression of Id2 in multiple mouse and (organotypic) human models of ILC, an event that is caused by a direct p120-catenin/Kaiso-dependent transcriptional de-repression of the canonical Kaiso binding sequence TCCTGCNA. Conversely, stable inducible restoration of E-cadherin expression in the ILC cell line SUM44PE inhibits Id2 expression and anoikis resistance. We show evidence that Id2 accumulates in the cytosol, where it induces a sustained and CDK4/6-dependent G0/G1 cell cycle arrest through interaction with hypo-phosphorylated Rb. Finally, we find that Id2 is indeed enriched in ILC when compared to other breast cancers, and confirm cytosolic Id2 protein expression in primary ILC samples. In sum, we have linked mutational inactivation of E-cadherin to direct inhibition of cell cycle progression. Our work indicates that loss of E-cadherin and subsequent expression of Id2 drive indolence and dissemination of ILC. As such, E-cadherin and Id2 are promising candidates to stratify low and intermediate grade invasive breast cancers for the use of clinical cell cycle intervention drugs.

Genomic profiling and pre-clinical modelling of breast cancer leptomeningeal metastasis reveals acquisition of a lobular-like phenotype

“…Others have demonstrated that ILC cells display anchorage-independent growth and anoikis resistance through increased levels of Rho/ROCK signalling mediated by the translocation of p120-catenin to the cytosol 48, 66 . In the nutrient-sparse CSF 69 , cells will have a survival advantage if they can enter a dormant, anoikis-resistant state via sustained G0/G1 cell cycle arrest 70 until they adapt to the harsh environment and re-enter proliferation.…”

Identifying General Tumor and Specific Lung Cancer Biomarkers by Transcriptomic Analysis

“…NR4A3 acts as a tumor suppressor in lung and breast cancer, favoring the activation of programmed cell death programs [ 83 ]. ID2 (DNA binding protein inhibitor 2) is a helix-loop-helix TF that positively regulates cancer cells’ proliferation [ 84 ], migration, invasion [ 85 ], and cell cycle progression, and also negatively regulates cancer cells’ differentiation and apoptosis [ 86 ], as well as other tumor suppressor genes [ 87 ]. ID2 has a role in the dedifferentiation of NSCLC cells, suggesting that it can be used as a prognostic marker [ 88 ].…”

Heterogeneity and versatility of the extracellular matrix during the transition from pleomorphic adenoma to carcinoma ex pleomorphic adenoma: cumulative findings from basic research and new insights

“…In malignant tumors, the cadherins family is downregulated causing a reduction in cell-cell adhesiveness (116). In breast cancer, tumor types of analogs to SGCs, E-cadherin has been associated with invasion and metastasis (117)(118)(119).…”