RUNX2 prompts triple negative breast cancer drug resistance through TGF-β pathway regulating breast cancer stem cells

Abstract

Triple-negative breast cancer (TNBC) stands out as the most aggressive subtype within the spectrum of breast cancer. The current clinical guidelines propose treatment strategies involving cytotoxic agents like epirubicin or paclitaxel. However, the emergence of acquired resistance frequently precipitates secondary tumor recurrence or the spread of metastasis. In recent times, significant attention has been directed toward the transcription factor RUNX2, due to its pivotal role in both tumorigenesis and the progression of cancer. Previous researches suggest that RUNX2 might be intricately linked to the development of resistance against chemotherapy, with its mechanism of action possibly intertwined with the signaling of TGF-β. Nevertheless, the precise interplay between their effects and the exact molecular mechanisms underpinning chemoresistance in TNBC remain elusive. Therefore, we have taken a multifaceted approach from in vitro and in vivo experiments to validate the relationship between RUNX2 and TGF-β and to search for their pathogenic mechanisms in chemoresistance. In conclusion, we found that RUNX2 affects chemoresistance by regulating cancer cell stemness through direct binding to TGF-β, and that TGF-β dually regulates RUNX2 expression. The important finding will provide a new reference for clinical reversal of the development of chemoresistance in breast cancer.

Keywords: Cancer stem cells; Chemoresistance; RUNX2; TGF-β; Triple negative breast cancer.

Fig. 1

RUNX2 and TGF-β are strongly associated with breast cancer malignancy.

Fig. 2

Influence of RUNX2 on the stemness of drug-resistant cells in triple-negative breast cancer.

Fig. 3

Influence of RUNX2 on resistance and proliferation of drug-resistant breast cancer cells in triple-negative breast cancer.

Fig. 4

The effect of shRUNX2 on the migration and invasion of drug-resistant cells in TNBC.

Fig. 5

Runx2 regulates TNBC chemoresistance by regulating TGF-β signaling pathway and transcription level expression of MDR1.

Fig. 6

TGF-β restores the effect of shRUNX2 on the stemness and metastatic ability of drug-resistant cells in TNBC.

Fig. 6

TGF-β restores the effect of shRUNX2 on the stemness and metastatic ability of drug-resistant cells in TNBC.

Fig. 7

RUNX2 binds directly to the TGF-βpromoter region.

Fig. 8

TGF-β play a dual role in regulating the expression of Runx2 in TNBC cells.

Fig. 9

A working model for the role of the RUNX2-TGF-β signaling axis in TNBC drug resistance.