Although c‑MYC contributes to tamoxifen resistance, it improves cisplatin sensitivity in ER‑positive breast cancer

Abstract

Tamoxifen (TAM) resistance is a major challenge in the treatment of estrogen receptor-positive (ER +) breast cancer. To date, to the best of our knowledge, there are only a few studies available examining the response of patients with TAM-resistant breast cancer to chemotherapy, and the guidelines do not specify recommended drugs for these patients. In the present study, TAM-resistant cells were shown to exhibit increased proliferation and invasion compared with the parent cells, and the increased expression of c-MYC was demonstrated to play an important role in TAM resistance. Furthermore, the TAM-resistant cells were significantly more sensitive to cisplatin compared with the parent cells, and the silencing of c-MYC expression desensitized the cells to cisplatin through the inhibition of the cell cycle. An increased c-MYC expression was observed in 28 pairs of primary and metastatic tumors from patients treated with TAM, and the clinical remission rate of cisplatin-based chemotherapy was significantly higher compared with other chemotherapy-based regimens in 122 patients with TAM resistant breast cancer. Taken together, the data of the present study demonstrated that although c-MYC was involved in TAM resistance, it increased the sensitivity of ER + breast cancer to cisplatin. Thus, cisplatin may be a preferred chemotherapeutic agent for the treatment of patients with TAM-resistant breast cancer, particularly in patients where the rapid control of disease progression is required.

Pharmacological Inhibition of CBP/p300 Blocks Estrogen Receptor Alpha (ERα) Function through Suppressing Enhancer H3K27 Acetylation in Luminal Breast Cancer

“…Although the gene effect data based on CRISPR for BT-474 are not available in the DepMap portal, high dependency on ESR1, MYC and CCND1 for cell viability of BT-474 are expected. ER, c-Myc, and Cyclin D1 are also known to promote tamoxifen resistance [ 15 ]. Notably, high MYC and CCND1 expression also correlates with poor relapse-free survival in BC patients treated with endocrine therapies (though it should be noted that the results for CCND1 are not as statistically significant as those for MYC, Figure S3A,B ).…”

“…Significantly, ER, c-Myc, and Cyclin D1 are known to play roles in driving tamoxifen resistance in BC cells in vitro and in patients. Indeed, tamoxifen-resistant BC cell lines have elevated expression of ER, c-Myc, and Cyclin D1 and inhibition of MYC restores tamoxifen sensitivity in these cells [ 15 ]. High MYC expression also correlates with poor relapse-free survival in patients treated with endocrine therapies [ 15 ].…”

“…Indeed, tamoxifen-resistant BC cell lines have elevated expression of ER, c-Myc, and Cyclin D1 and inhibition of MYC restores tamoxifen sensitivity in these cells [ 15 ]. High MYC expression also correlates with poor relapse-free survival in patients treated with endocrine therapies [ 15 ]. Additionally, Cyclin D1 can activate ER function independently of estrogen, which apparently is not inhibited by anti-estrogen therapies [ 16 ].…”

Upregulation of PI3K/AKT/PTEN pathway is correlated with glucose and glutamine metabolic dysfunction during tamoxifen resistance development in MCF-7 cells

“…c-MYC is known to be over expressed in breast cancer, and its involvement in glutamine uptake and degradation is well reported, as it stimulates surface transporters and glutamine synthetase suppression 29 . Chen et al reported that MCF-7 tamoxifen resistant model produced by treating the cells with increased concentrations of 4-hydroxytamoxifen for 8 months expressed more c-MYC and enhanced resistance 30 . Upon comparison with the models produced in this study, much less concentrations of tamoxifen were used with no significant c-MYC gene expression and over expressed GLUL was observed.…”

Non-Genomic Actions of Estrogens on the DNA Repair Pathways Are Associated With Chemotherapy Resistance in Breast Cancer

“…In the cell cycle arrest, E 2 play a relevant role in resistance induction since some reports indicate that the ERα stimulates cell cycle progression through positive transcriptional regulation of cyclin D, since ERα interacts to an AMPc-response element (CRE) present in the cyclin D gene promoter, and induces the synthesis of the c-myc oncogene which controls the expression of cyclin D1 ( 70 ). The induction of c-Myc by E 2 is also generated by the binding of ERα to an ERE, present in the promoter region of the c-myc gene ( 60 , 71 ). The E 2 -ER rapidly activates the cyclin E/CDK2 complex accelerating the transition from G1 to S; furthermore, ER negatively regulates the expression of the p21 inhibitor to induce the progression of the cell cycle ( 72 ).…”