On the other hand, studies in ER-negative breast cancer SkBr3 cells showed that estrogen/GPER signaling is able to induce HIF-1α expression and activity [165] as well as Notch-1 mRNA levels and NICD accumulation [6], suggesting that estrogen/GPER may strengthen EMT by simultaneously inducing Notch and HIF-1α signaling pathways in normoxic breast cancer cells (Figure 2). Here, NOTCH1 is linked to breast carcinoma.