ID1 and ID4 Are Biomarkers of Tumor Aggressiveness and Poor Outcome in Immunophenotypes of Breast Cancer

SIMPLE SUMMARY: Inhibitor of differentiation (ID) proteins are essential to promote proliferation during embryonic development, but they are silenced in most adult tissues. Evidence to date shows ID1 expression in many tumor types, including breast cancer. However, the role of the remaining ID family members, especially ID4, in breast cancer remains unclear. In this work, we aimed to assess the four ID genes expression in breast cancer cell lines and a long series of breast cancer samples and correlate them with clinicopathological features and patients’ survival. We observed a significantly higher expression of ID4 in tumor cell lines than the healthy breast epithelium cell line. We confirmed that the overexpression of ID1 and ID4 correlated with more aggressive phenotypes and poor survival in breast cancer patients’ samples. Our results support the importance of ID proteins as targets for the development of anti-cancer drugs. ABSTRACT: Inhibitor of differentiation (ID) proteins are a family of transcription factors that contribute to maintaining proliferation during embryogenesis as they avoid cell differentiation. Afterward, their expression is mainly silenced, but their reactivation and contribution to tumor development have been suggested. In breast cancer (BC), the overexpression of ID1 has been previously described. However, whether the remaining ID genes have a specific role in this neoplasia is still unclear. We studied the mRNA expression of all ID genes by q RT-PCR in BC cell lines and 307 breast carcinomas, including all BC subtypes. Our results showed that ID genes are highly expressed in all cell lines tested. However, ID4 presented higher expression in BC cell lines compared to a healthy breast epithelium cell line. In accordance, ID1 and ID4 were predominantly overexpressed in Triple-Negative and HER2-enriched samples. Moreover, high levels of both genes were associated with larger tumor size, histological grade 3, necrosis and vascular invasion, and poorer patients’ outcomes. In conclusion, ID1 and ID4 may act as biomarkers of tumor aggressiveness and worse prognosis in breast cancer, and they could be used as potential targets for new treatments discover.