Low-molecular-weight cyclin E deregulates DNA replication and damage repair to promote genomic instability in breast cancer

Low-molecular-weight cyclin E (LMW-E) is an N-terminus deleted (40 amino acid) form of cyclin E detected in breast cancer, but not in normal cells or tissues. LMW-E overexpression predicts poor survival in breast cancer patients independent of tumor proliferation rate, but the oncogenic mechanism of LMW-E and its unique function(s) independent of full-length cyclin E (FL-cycE) remain unclear. In the current study, we found LMW-E was associated with genomic instability in early-stage breast tumors ( n = 725) and promoted genomic instability in human mammary epithelial cells (hMECs). Mechanistically, FL-cycE overexpression inhibited the proliferation of hMECs by replication stress and DNA damage accumulation, but LMW-E facilitated replication stress tolerance by upregulating DNA replication and damage repair. Specifically, LMW-E interacted with chromatin and upregulated the loading of minichromosome maintenance complex proteins (MCMs) in a CDC6 dependent manner and promoted DNA repair in a RAD51- and C17orf53-dependent manner. Targeting the ATR-CHK1-RAD51 pathway with ATR inhibitor (ceralasertib), CHK1 inhibitor (rabusertib), or RAD51 inhibitor (B02) significantly decreased the viability of LMW-E–overexpressing hMECs and breast cancer cells. Collectively, our findings delineate a novel role for LMW-E in tumorigenesis mediated by replication stress tolerance and genomic instability, providing novel therapeutic strategies for LMW-E–overexpressing breast cancers. Low-molecular-weight cyclin E (LMW-E) overexpression promotes genomic instability in human mammary epithelial cells and associates with genomic instability in early-stage breast tumors. Full-length cyclin E (FL-cycE) overexpression leads to accumulation of replication stress, DNA damage, and ultimately cell death. Mechanistically, LMW-E upregulates the expression of CDC6, RAD51, and C17orf53. LMW-E, but not FL-cycE, facilitates replication stress tolerance by promoting pre-replication complex assembly in a CDC6 dependent manner and DNA damage repair in a RAD51- and C17orf53-dependent manner. Targeting the ATR-CHK1-RAD51 pathway with small molecule inhibitors significantly decreased LMW-E–overexpressing cell viability. In breast tumor samples, positive LMW-E status independently predicts genomic instability and tumor recurrence.