Steroid hormone receptors, including estrogen receptor (ER) and progesterone receptor (PR), have been used as critical indicators for endocrine therapy and prognosis in breast cancer (BC) since the mid-1970s.^1,2 Detection of ER and PR is recommended in patients with newly diagnosed BC in clinical practice.³ Compared with hormone receptor–negative BC, hormone receptor–positive BC is associated with less aggressive clinicopathological features and a better prognosis because of the benefits from endocrine therapy.⁴ The PR is encoded by an estrogen-regulated gene, and its synthesis requires estrogen and ER; therefore, ER-positive tumors are commonly PR positive, whereas ER-negative tumors are usually PR negative.⁵ However, some tumors are single hormone receptor positive (ER positive/PR negative or ER negative/PR positive) and are thought to be biologically and clinically different from double hormone receptor–positive/double hormone receptor–negative subtypes, although the cause of single hormone receptor–positive BC remains unclear.^5-7 Patients with single hormone receptor–positive tumors have an intermediate prognosis between double hormone receptor–positive (best survival) and double hormone receptor–negative (worst survival) tumors, whereas there is no survival difference between patients who have ER-positive/PR-negative tumors and patients who have ER-negative/PR-positive tumors.⁷ A statistically significant difference in prognosis is only detected between single hormone receptor–positive and double hormone receptor–positive subtypes in ERBB2 (formerly HER2)–negative BC.⁸ Therefore, it is unknown whether ER-positive/PR-negative and ER-negative/PR-positive tumors are biologically and clinically distinct subtypes of BC.

E2Fs, as a family of pivotal transcription factors, have been implicated in multiple biological functions in human cancer; however, the expression and prognostic significance of E2Fs in breast cancer remains unknown. In the present study, the mRNA expression patterns of E2Fs in breast cancer were investigated with Oncomine and The Cancer Genome Atlas data. Prognostic values of E2Fs for patients with breast cancer were determined using the Kaplan-Meier plotter database. The results strongly indicated that E2F1, E2F2, E2F3, E2F5, E2F7 and E2F8 were overexpressed in patients with breast cancer, whereas E2F4 and E2F6 exhibited no expression difference between patients with cancer and healthy controls. In survival analyses, elevated E2F1, E2F3, E2F5, E2F7 and E2F8 expression levels were significantly associated with lower overall survival, relapse-free survival (RFS), distant metastasis-free survival (DMFS) or post-progression survival for patients with breast cancer. Furthermore, high expression of E2F4 indicated improved RFS but reduced DMFS. Subgroup analyses based on four clinicopathological factors further revealed that E2Fs were associated with the prognosis of patients with breast cancer in an estrogen receptor-, progesterone receptor-, human epidermal growth factor 2-and lymph node status-specific manner. These data indicated that E2Fs may serve as promising biomarkers and therapeutic targets for breast cancer.