β2M silencing downregulated p-SGK1/SGK1 levels and Bcl-2 expression, and β2M overexpression downregulated p-CREB/CREB and significantly upregulated p-SGK1/SGK1 levels and Bcl-2 expression, and both resulting processes did not affect HER2, HIF-1α, VEGF, and ERK signaling in ER+ breast cancer cells with HER2−. The gene discussed is CREB1; the disease is breast cancer.