Log-linear scaling of TRPV4-KCNN4 transcripts tunes ROCK-dependent mechanotransduction in a DCIS progression model

Mechanotransduction converts mechanical stress into cellular responses, yet how transcript abundance sets mechanotransduction capacity remains unclear. Using an isogenic MCF10A breast epithelial progression series in which crowding functionally inhibits plasma-membrane TRPV4 and triggers pro-invasive motility, we quantified how pathway mRNA levels relate to stress-evoked single-cell motility. TRPV4 (Ca{superscript 2}-permeable mechanosensor) and KCNN4 (Ca{superscript 2}-activated K channel) mRNA levels scaled log-linearly with motility under hyperosmotic stress or pharmacologic TRPV4 inhibition (both engaging the crowding-induced pro-invasive motility program) across a [~]600-fold TRPV4 mRNA range including isogenic and patient-derived DCIS lines (TRPV4: R{superscript 2}=0.89-0.92; KCNN4: R{superscript 2}=0.81-0.94). In contrast, bulk TRPV4 protein did not correlate with motility. Mechanistically, ROCK inhibition abolished stress-induced cortical actin-myosin organization and associated motility gains, identifying ROCK-dependent cortical contractility as a downstream effector. Notably, log-linear scaling was restricted to membrane channels and did not extend to tested cytosolic effectors, suggesting hierarchical transcript regulation may shape heterogeneous DCIS stress responsiveness in this model system.