Breast cancer is the second most common type of cancer and a remarkably heterogeneous disease, and it is divided into four types based on the expression of ER, PR, and HER2 [
24]. Each type of breast cancer has very complex molecular characteristics. ER
+ and ER
− breast cancers differ in the expression of thousands of genes and show distinct patterns of mutations and alterations in the DNA copy number [
26‐
28]. Prognosis and chemotherapy response of patients with ER
+ and ER
− breast cancer are associated with different biological processes [
29]. β2M has been reported as a growth-, angiogenesis-, EMT-, and bone metastasis-stimulating factor in various solid tumor malignancies [
9], but inconsistent effects on breast cancer have been reported [
14,
16‐
20]. Our previous study found that β2M expression demonstrated a significant difference in four types of breast cancer. Its protein expression was significantly associated with ER expression in breast cancer tissues, and it had distinct regulatory effects on HER2 and Bcl-2 expression in ER
+ PR
+ HER2
− and ER
− PR
− HER2
− cell lines [
3]. However, the molecular regulatory mechanism of β2M on ER
+ and ER
− breast cancers with HER2
− is poorly understood.
In this study, our results demonstrated the following. First, β2M activates SGK1 signaling and upregulates Bcl-2 expression, and do not affect HER2, HIF-1α, VEGF, and ERK signaling in ER
+ breast cancer cells with HER2
−. A previous study has reported that SGK1 signaling promotes cell survival, and SGK1 activation is dependent on the activation of PI3K and the production of PtdIns (3,4,5) P3, which could induce phosphorylation of SGK1 at its hydrophobic motif (Ser422) that in turn promotes the interaction of SGK1 with phosphoinositide-dependent kinase 1 (PDK1). Then, PDK1 activates SGK1 by phosphorylating the T-loop residue (Thr256) [
30]. Subsequently, a model suggested that SGK1-Ser422 phosphorylation requires mTOR complex 1 (mTORC1) activity in ER
+ MCF-7 and T47D cells [
31]. Therefore, β2M may promote the survival of tumor cells through the mTORC1/SGK1/Bcl-2 signaling pathway in ER
+ breast cancer cells with HER2
− (MCF-7 and T47D). Second, β2M inhibits CREB signaling and the expression of VEGF protein and activates ERK signaling, but does not affect HIF-1α and SGK1 signaling in ER
− breast cancer cells with HER2
−. CREB, a transcription factor, is involved in the tumorigenicity of HER2/Neu-overexpressing tumor cells [
32,
33]; VEGF, a CREB target gene, is associated with tumor angiogenesis, metastatic growth, and poor prognosis in breast cancer [
34‐
36]. Activation of ERK survival signaling can be triggered by β2M treatment [
11] or overexpression [
12] in human renal cell carcinoma SN12C cells. Therefore, β2M may inhibit the survival of tumor cells through the inhibition of CREB/VEGF signaling, and promote the survival of tumor cells through the activation of ERK signaling in ER
− breast cancer cells with HER2
−. The reason behind the observed opposite regulatory effects of β2M on ER
− breast cancer cells with HER2
− may be that the triple-negative breast cancer is a special type of breast cancer that has special biological behavior and a very complex regulatory mechanism. Third, β2M exhibits different regulatory effects on CREB and p-CREB in the cell lines of ER
+ breast cancer with HER2
− (MCF-7 and T47D), and HER2 and Bcl-2 in the cell lines of ER
− breast cancer with HER2
− (MDA-MB-231 and Hs578T), which may be due to the fact that breast cancer has a very complex molecular regulatory mechanism, and every type of breast cancer has several subtypes, and these signaling molecules may be regulated by other pathways in corresponding subtypes of breast cancer. Fourth, β2M is positively correlated with p-CREB, p-SGK1, and Bcl-2 and has no correlation with HIF-1α, VEGF and p-ERK1/2, and p-SGK1 has a significantly positive correlation with Bcl-2 in cancer tissues of patients with luminal A breast cancer, which agrees with the results obtained from the same molecular types of breast cancer cells except CREB signaling. However, β2M expression shows no significant correlation with HIF-1α, p-CREB, VEGF, p-SGK1, p-ERK1/2, and Bcl-2 except for VEGF, which shows a strong positive correlation with Bcl-2 in cancer tissues of patients with basal-like breast cancer, thereby showing discordance with the results obtained from the same molecular types of breast cancer cells. One possible reason is that large differences may exist among cancer cell lines and tissue samples, particularly in terms of its molecular genome [
37,
38], and cell lines only mirror some but not all of the molecular properties of primary tumors [
24]. In addition, VEGF protein is upregulated, whereas VEGF mRNA is downregulated following β2M silencing in Hs578T cells. Previous study has also shown that some proteins are negatively correlated with the mRNA expression in lung adenocarcinomas, which may reflect negative feedback on the mRNA or the protein or the presence of other regulatory influences [
39]. Therefore, VEGF protein may have a negative feedback on VEGF mRNA, resulting in the rapid degradation and downregulation of the mRNA when increasing to the peak following β2M silencing. Consequently, β2M may promote tumor survival through the SGK1/Bcl-2 signaling pathway in ER
+ breast cancer with HER2
− and have no regulatory effects in ER
− breast cancer with HER2
−. It is possible that the regulatory function of β2M is correlated with ER expression in HER2
− breast cancer. The regulatory mechanism of β2M in HER2
− breast cancer needs to be further investigated.