Abstract
E2F transcription factors play critical roles in the cell cycle. Therefore, their activity is expected to reflect tumor aggressiveness and responsiveness to therapy. We scored 3905 tumors of nine breast cancer cohorts for this activity based on their gene expression for the Hallmark E2F targets gene set. As expected, tumors with a high score had an increased expression of cell proliferation-related genes. A high score was significantly associated with shorter patient survival, greater MKI67 expression, histological grade, stage, and genomic aberrations. Furthermore, metastatic tumors had higher E2F scores than the primary tumors from which they arose. Although tumors with a high score had greater infiltration by both pro- and anti-cancerous immune cells, they had an increased expression of immune checkpoint genes. Estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative cancer with a high E2F score achieved a significantly higher pathological complete response (pCR) rate to neoadjuvant chemotherapy. The E2F score was significantly associated with the expression of cyclin-dependent kinase (CDK)-related genes and strongly correlated with sensitivity to CDK inhibition in cell lines. In conclusion, the E2F score is a marker of breast cancer aggressiveness and predicts the responsiveness of ER-positive/HER2-negative patients to neoadjuvant chemotherapy and possibly to CDK and immune checkpoint inhibitors.
Highlights
Cell cycle progression is a critical component of cell proliferation, and continuous proliferation is one of the hallmarks of cancer [1]
We examined the tumor expression of the other Hallmark gene sets using the gene set enrichment analysis (GSEA) method
We found that Indel and single nucleotide variation (SNV) neoantigen loads were associated with a high E2F pathway score (Figure 1C; p = 0.006 and 0.047 respectively)
Summary
Cell cycle progression is a critical component of cell proliferation, and continuous proliferation is one of the hallmarks of cancer [1]. Components regulating the E2F pathway have been identified in nearly every human malignancy, and many of them including E2F transcription factors themselves play major roles in cancer progression, metastasis, and treatment response of breast cancer [2]. The transcriptional activity of E2Fs is regulated through cyclin-dependent kinase (CDK) 4/6-cyclin D complexes that function as a cell cycle checkpoint, phosphorylating the retinoblastoma (Rb) tumor suppressor protein and thereby releasing E2F1 from Rb to cause the transcription of G1-S transition and S phase genes. These E2F target genes encode proteins involved in DNA replication, cyclins, and the E2F transcription factors themselves. The dysregulated expression of E2Fs is often observed in various malignances, including breast cancer
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