Journal
CELL CYCLE
Volume 19, Issue 20, Pages 2589-2599Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15384101.2020.1804720
Keywords
c-Myc; cyclin E; breast cancer
Categories
Funding
- NIH [R01 CA202634, P50 CA168504, R50 CA243769]
- Sichuan Provincial People's Hospital
- China Scholarship Council
- Studienstiftung des deutschen Volkes (German Academic Scholarship Foundation)
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Basal-like triple-negative breast cancers frequently express high levels of c-Myc. This oncoprotein signals to the core cell cycle machinery by impinging on cyclin E. High levels of E-type cyclins (E1 and E2) are often seen in human triple-negative breast tumors. In the current study, we examined the requirement for E-type cyclins in the c-Myc-driven mouse model of breast cancer (MMTV-c-Myc mice). To do so, we crossed cyclin E1- (E1(-/-)) and E2- (E2(-/-)) deficient mice with MMTV-c-Myc animals, and observed the resulting cyclin E1(-/-)/MMTV-c-Myc and cyclin E2(-/-)/MMTV-c-Myc females for breast cancer incidence. We found that mice lacking cyclins E1 or E2 developed breast cancers like their cyclin Ewild-type counterparts. In contrast, further reduction of the dosage of E-cyclins in cyclin E1(-/-)E2(+/-)/MMTV-c-Myc and cyclin E1(+/-)E2(-/-)/MMTV-c-Myc animals significantly decreased the incidence of mammary carcinomas, revealing arole for E-cyclins in tumor initiation. We also observed that depletion of E-cyclins in human triple-negative breast cancer cell lines halted cell cycle progression, indicating that E-cyclins are essential for tumor cell proliferation. In contrast, we found that the catalytic partner of E-cyclins, the cyclin-dependent kinase 2 (CDK2), is dispensable for the proliferation of these cells. These results indicate that E-cyclins, but not CDK2, play essential and rate-limiting roles in driving the proliferation of c-Myc overexpressing breast cancer cells.
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