Invasive lobular breast carcinoma (ILC) is a low grade and mostly chemo-refractory luminal-type breast cancer that has been linked to sustained proliferative quiescence and long-term latency relapses (15-20 years). Loss of E-cadherin causes metastatic lobular breast cancer, partly through acquisition of anchorage independence. It is however still unknown how ILC cells control the balance between proliferative indolence and cell cycle re-entry at the metastatic site. We show here that E-cadherin loss leads to upregulation of Id2 through p120-catenin/Kaiso-dependent transcriptional derepression. Anchorage independent conditions further exacerbate p120-driven Id2 expression, leading to a sustained G0/G1 cell cycle arrest through binding of cytosolic Id2 to hypo-phosphorylated Rb. Intriguingly, we find that E-cadherin inactivation causes increased sensitivity to CDK4/6 inhibition in mouse and human breast cancer cell lines and primary tumor organoids. Finally, we find that Id2 expression is elevated in human ILC when compared to ductal breast cancers. Based on these data, we propose that combined E-cadherin loss and cytosolic Id2 expression can be used for the differential diagnosis of ILC and represent a candidate predictive biomarker pair for cell cycle targeting drug efficacy.

Citation Format: Max Antonius Klaus Rätze, Thijs Koorman, Thijmen Sijnesael, Blessing Bassey-Archibong, Robert van de Ven, Lotte Enserink, Daan Visser, Sridevi Jaksani, Elvira Bakker, François Richard, Andrew Tutt, Rebecca Steele, Stephen Pettitt, Christopher J. Lord, Amanda Fitzpatrick, Clare Isacke, Paul J. van Diest, Christine Desmedt, Juliet M. Daniel, Patrick W.B. Derksen. E-cadherin loss drives Id2-dependent dampening of cell cycle progression and predicts increased susceptibility to CDK4/6 inhibition in lobular breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB246.