Ligand-dependent transcriptional heterogeneity in cell cycle gene expression delays G1/S entry.

ErbB ligands activate distinct receptor dimers that regulate cell proliferation, but how they influence cell-cycle commitment remains unclear. Here, we show that EGF and HRG induce different modes of G1/S progression in ErbB2-amplified BT474 breast cancer cells. Unexpectedly, HRG, despite activating the more potent ErbB2-ErbB3 heterodimer, failed to accelerate G1/S progression; instead, EGF promoted earlier passage through the restriction point and faster S-phase entry. Mechanistically, EGF drove rapid and coordinated cell-cycle progression through ERK-FOS signaling, whereas HRG induced sustained MYC activity, elevated transcriptional heterogeneity, and caused extensive rewiring of cell-cycle regulatory networks. Together, these findings reveal that ligand-specific ErbB signaling controls not only the timing of cell-cycle entry but also the transcriptional architecture that governs proliferative fate decisions.