Hox-C12 coordinates β 2 -adrenoceptor coupling to a cAMP/calcium feedforward loop to drive invasion in triple-negative breast cancer

Noradrenaline released from sympathetic neurons accelerates cancer metastasis by activating β₂-adrenergic receptors (β₂-adrenoceptors) on tumor cells to promote invasion. We previously showed that the β₂-adrenoceptor promotes invasive behavior in a metastatic triple-negative breast cancer (TNBC) cell line by activating a cAMP- and calcium-mediated feedforward loop. Here, we found this mechanism in most TNBC lines that have an active β₂-adrenoceptor. Integrated analysis of transcriptomic datasets revealed HOXC12, which encodes a developmental homeobox transcription factor, as the most discriminating gene separating cell lines with the feedforward loop and those without it. The high expression of HOXC12 did not correlate with transcriptional changes in integral proteins associated with cAMP or calcium signaling, and immunostaining showed cytosolic localization of Hox-C12, suggesting that it played a nontranscriptional role. Knocking out HOXC12 prevented β₂-adrenoceptor-mediated calcium signaling and invasion in cultured TNBC cells. In basal breast cancers, HOXC12 expression in tumors negatively correlated with overall and disease-free survival in patients. These findings identify a key mediator, Hox-C12, in the coordination of invasion driven by cAMP and calcium signaling in β₂-adrenoceptor-responsive TNBC cells.