Regulatory interplay of cyclin D1 and INSM1 in suppressing INSL6 expression: Implications for breast cancer biology

Cyclin D1, a key regulator of the G1-to-S phase cell cycle transition, is frequently amplified or overexpressed in breast cancer, contributing to tumorigenesis. Beyond its canonical role in cell cycle regulation, Cyclin D1 forms a complex with INSM1, a zinc-finger transcriptional repressor implicated in neuroendocrine differentiation. Here, we identify insulin-like peptide 6 (INSL6) as a novel transcriptional target of the Cyclin D1–INSM1 complex. Chromatin immunoprecipitation assays revealed INSM1 binding near the transcription start site of the INSL6 gene, and luciferase reporter assays confirmed Cyclin D1-mediated suppression of INSL6 promoter activity. Furthermore, Cyclin D1 overexpression reduced INSL6 mRNA levels, while Cyclin D1 knockdown reversed this effect, highlighting its potential regulatory role. Given the observed association of low INSL6 expression with shorter relapse-free survival, these findings suggest that the Cyclin D1–INSM1 axis may contribute to tumor progression through INSL6 repression. This study provides new insights into the non-canonical functions of Cyclin D1 in breast cancer and identifies potential therapeutic targets within this regulatory pathway.