Mcam stabilizes a luminal progenitor-like breast cancer cell state via Ck2 control and Src/Akt/Stat3 attenuation

Abstract

AbstractBreast cancers are categorized into subtypes with distinctive therapeutic vulnerabilities based on expression of clinically targetable receptors and other genes that mimic cell types of the normal gland. Here, we tested the role of the plasma membrane-integral glycoprotein Mcam in breast cancer cell state control and tumorigenicity using a murine tumor cell line (Py230), that exhibits lineage and tumor subtype plasticity. Mcam knockdown (KD) Py230 cells exhibit increased mesenchymal morphology, migration, Src/Fak/Mapk/Paxillin adhesion complex signaling and Pi3K/Akt, Stat3 and Stat5a activation. They also show a transcriptional switch from a hormone-sensing/luminal progenitor state toward alveolar and basal cell states. Reminiscent of archival human breast cancers and patient derived organoid expression data associated with endocrine resistant disease, Mcam KD Py230 cells were refractory to growth inhibition by tamoxifenin vitro. Endocrine resistance and cell state change resulting from Mcam KD were reversed by inhibition of Stat3 or the upstream activating kinase Ck2. Finally, while Mcam KD cells exhibited more aggressive phenotypesin vitro, they showed reduced tumorigenicity and lacked Sox10+/neural crest cell state acquisitionin vivo. Our studies uncover breast cancer cell state plasticity dependent on Mcam, Ck2, and Stat3 with implications for progression, evasion of targeted therapies and combination therapy design.