# IGFBP-6 regulates breast cancer cell cycle progression by promoting exit out of G1

## TL;DR

This study shows that IGFBP-6 helps breast cancer cells progress through the cell cycle by reducing G1 phase and increasing G2/M transition.

## Contribution

The study reveals a novel role of IGFBP-6 in regulating breast cancer cell cycle progression and interferon signaling.

## Key findings

- IGFBP-6 knockdown increases G1 phase and decreases G2/M phase in T47D breast cancer cells.
- IGFBP-6 knockdown activates interferon signaling and reduces G2/M-related pathways.
- Cyclin B1 accumulation is reduced in MDA-MB-231 cells after IGFBP-6 knockdown.

## Abstract

While the contribution of the IGF-signaling axis in breast cancer is well-documented, the role of IGFBP-6 in breast carcinogenesis has not been extensively studied. In general, insulin-like growth factor binding protein-6 (IGFBP-6) sequesters insulin-like growth factor 2 (IGF-2) to attenuate activation of its cognate receptor IGF-1R. To reveal previously unknown mechanisms of breast cancer modulation by IGFBP-6 in breast cancer, proteomic analysis was performed in T47D cells after IGFBP-6 knockdown. Comparing protein expression and phosphosites after knockdown by unique siRNA sequences with a negative control and subsequent pathway analysis, a decrease in IGFBP-6 expression resulted in activation of interferon signaling pathways and a decrease in pathways involved in the G2/M cell cycle transition. A subset of the proteins identified in each cell regulatory pathway was validated by immunoblotting for specific proteins after IGFBP-6 knockdown. Cell cycle analysis showed that IGFBP-6 knockdown in Hormone Receptor Positive T47D breast cancer cells resulted in an increased number of cells in the G1 phase and a decrease in cells in G2, indicating a role for IGFBP-6 in cell cycle regulation. Knockdown of IGFBP-6 in a triple-negative breast cancer cell line, MDA-MB-231, also resulted in a decrease in Cyclin B1 accumulation, demonstrating that our observations are not cell line specific. Taken together, our results demonstrate that IGFBP-6 regulates cell cycle progression in breast cancer cells and interferon signaling in hormone-positive cells.