EGFR and breast carcinoma: Thus, the authors suggest that ERK1/2 can exist either upstream or downstream of SphK1 signaling, as it “has a dual role in initiation and amplification of a positive-feedback signaling loop across E2, SphK1 and EGFR in breast cancer cells [37].” The authors concluded that S1P and its receptors are critical in the E2-stimulated activation of EGFR, where SphK1 couples or mediates signaling between E2, S1P and EGF in a “criss-cross” manner [37].