SIRT4 enhances the sensitivity of ER‐positive breast cancer to tamoxifen by inhibiting the IL‐6/STAT3 signal pathway

Abstract

Recent advances in endocrine therapy have improved the prospects for estrogen receptor‐positive breast cancer. Tamoxifen is an effective drug for patients with estrogen receptor‐positive breast cancer, but the development of resistance is common. Therefore, discovering ways to enhance the sensitivity of cancer cells to tamoxifen may help improve breast cancer treatment. We studied the biological role of sirtuin 4 (SIRT4) in tamoxifen‐treated MCF7 and T47D cells. The levels of the MYC proto‐oncogene (MYC) and cyclin D1 (CCND1) were detected by western blotting and quantitative reverse transcription‐polymerase chain reaction in breast cancer cells with SIRT4 overexpression or depletion. Immunofluorescence and western blotting were used to assess the phosphorylation status of signal transducer and activator of transcription 3 (STAT3). SIRT4 overexpression decreased the half maximal inhibitory concentration of tamoxifen in MCF7 and T47D cells, while its depletion increased it. Thus, SIRT4 enhances the sensitivity of breast cancer cells to tamoxifen. Moreover, western blotting revealed decreased STAT3 phosphorylation after SIRT4 transfection. The transcription and translation of MYC and CCND1, target genes of the STAT3 pathway, were also blocked. Immunofluorescence revealed that pathway activation and nuclear STAT4 translocation were suppressed when SIRT4 was overexpressed. Furthermore, the effects of SIRT4 overexpression or depletion on proliferation could be offset by STAT3 activation or inhibition. Taken together, these results demonstrate that SIRT4 enhances the tamoxifen sensitivity of breast cancer cells by inhibiting the STAT3 signaling pathway. With this knowledge, therapeutic strategies with reduced drug resistance risk may be developed.

Functions of mammalian SIRT4 in cellular metabolism and research progress in human cancer (Review)

“…A study also demonstrated that SIRT4 is a substrate of ubiquitin-like with plant homeodomain and ring finger domains 1 (UHRF1) and negatively regulated aerobic glycolysis, tumor proliferation, and metastasis of pancreatic cancer cells ( 95 ). A recent study also suggested that SIRT4 overexpression could heighten the sensitivity of ER-positive breast cancer to tamoxifen via inhibiting the interleukin-6/STAT3 pathway ( 102 ).…”

Paeoniflorin Sensitizes Breast Cancer Cells to Tamoxifen by Downregulating microRNA-15b via the FOXO1/CCND1/β-Catenin Axis

“… 4 Unfortunately, endocrine resistance interferes with the therapeutic effects of Tam, since approximately 30% of women develop local recurrence or distant metastasis despite the initial beneficial response. 5 …”

Heregulin Drives Endocrine Resistance by Altering IL-8 Expression in ER-Positive Breast Cancer

“…Thus, in HRG-overexpressing ER+/HER2-negative cells, specific neutralization of IL-8 bioactivity likewise reduces the ability of HRG overexpression to increase the non-genomic (e.g., MAPK- and PI3K-induced) unliganded transcriptional activity of ERα. The finding that anti-IL-8 treatment reduced but did not completely block the E 2 -independent hyperactivity of ERα in the continuous presence of up-stream oncogenic stimuli such as HRG suggests a need not only for combined treatment with drugs capable of impeding ligand-induced HER2/HER3 signaling (e.g., pertuzumab) but also the potential involvement of additional HRG-driven ERα co-activating cytokines (e.g., IL6, which is known to be repressed by E 2 -driven activation of ERα but drives endocrine therapy resistance by various mechanisms including direct transcriptional activation of ERα [ 50 , 51 , 52 , 53 , 54 , 55 , 56 ]). In this complex scenario of multiple cytokines driving endocrine resistance in HRG-overexpressing ER+ breast cancer cells, the sole blockade of IL-8 bioactivity might become inadequate in the presence of an augmented availability of IL-6 downstream of the HRG-activated HER2/HER2 oncogenic unit.…”