Ceramide kinase confers tamoxifen resistance in estrogen receptor-positive breast cancer by altering sphingolipid metabolism
- Pharmacol Res. 2022 Nov 18;106558. doi: 10.1016/j.phrs.2022.106558.
- 1. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China 510120.
- 2. Department of Breast Cancer, Cancer Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China 510080.
- 3. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China 510120; Department of Otolaryngology, Head and Neck Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China 510120.
- 4. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China 510120; Department of Ultrasound, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China 510120.
- 5. Department of Breast Cancer, Cancer Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China 510080. Electronic address: [email protected].
- 6. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China 510120; Laboratory Department, Dongguan Children's Hospital Affiliated to Guangdong Medical University, Dongguan, China 523000. Electronic address: [email protected].
- 7. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China 510120. Electronic address: [email protected].
Dysregulated sphingolipid metabolism contributes to ER+ breast Cancer progression and therapeutic response, whereas its underlying mechanism and contribution to tamoxifen resistance (TAMR) is unknown. Here, we establish sphingolipid metabolic enzyme CERK as a regulator of TAMR in breast Cancer. Multi-omics analysis reveals an elevated CERK driven sphingolipid metabolic reprogramming in TAMR cells, while high CERK expression associates with worse patient prognosis in ER+ breast Cancer. CERK overexpression confers tamoxifen resistance and promotes tumorigenicity in ER+ breast Cancer cells. Knocking out CERK inhibits the orthotopic breast tumor growth of TAMR cells while rescuing their tamoxifen sensitivity. Mechanistically, the elevated EHF expression transcriptionally up-regulates CERK expression to prohibit tamoxifen-induced sphingolipid ceramide accumulation, which then inhibits tamoxifen-mediated repression on PI3K/Akt dependent cell proliferation and its driven p53/Caspase-3 mediated Apoptosis in TAMR cells. This work provides insight into the regulation of sphingolipid metabolism in tamoxifen resistance and identifies a potential therapeutic target for this disease.