Ca2+ is an essential and ubiquitous second messenger. Changes in cytosolic Ca2+ trigger events critical for tumorigenesis, such as cellular motility, proliferation, and apoptosis. We show that an isoform of Secretory Pathway Ca2+-ATPase, SPCA2, is upregulated in breast cancer-derived cells and human breast tumors, and suppression of SPCA2 attenuates basal Ca2+ levels and tumorigenicity. Contrary to its conventional role in Golgi Ca2+ sequestration, expression of SPCA2 increased Ca2+ influx by a mechanism dependent on the store-operated Ca2+ channel Orai1. Unexpectedly, SPCA2-Orai1 signaling was independent of ER Ca2+ stores or STIM1 and STIM2 sensors and uncoupled from Ca2+-ATPase activity of SPCA2. Binding of the SPCA2 amino terminus to Orai1 enabled access of its carboxyl terminus to Orai1 and activation of Ca2+ influx. Our findings reveal a signaling pathway in which the Orai1-SPCA2 complex elicits constitutive store-independent Ca2+ signaling that promotes tumorigenesis. Display omitted ► SPCA2, but not SPCA1, is highly upregulated in breast cancer cells ► SPCA2 elicits elevation of basal Ca2+ levels mediated by Orai1 ► SPCA2 functions independently of its ATPase activity or store-operated Ca2+ entry ► SPCA2-induced Ca2+ signaling is necessary for cell proliferation and tumorigenesis