Considering that ER-positive HER2-negative breast cancer patients have particularly high S1P levels in cancer tissues compared with other subtypes and that previous basic studies have shown that “inside-out” signaling of S1P contributes to the signaling of the ER non-genomic pathway, S1P is predicted to play an important role in ER-positive breast cancer in combination with estrogen signaling [82]. This evidence concerns the gene ESR1 and breast cancer.