Runx1 activates the transformation of adipocytes into cancer-associated adipocytes by downregulating Plin1

Adipocytes play a pivotal role in the breast tumor microenvironment, with the capacity to differentiate into cancer-associated adipocytes (CAAs) under the influence of breast cancer cells. This transformation significantly contributes to the formation and progression of breast cancer; however, the mechanisms underlying this interaction remain poorly understood. This study aims to illuminate these interactions by establishing an in vitro co-culture system of mature adipocytes and breast cancer cells. RNA sequencing analysis identified elevated runt-related transcription factor 1 (Runx1) expression in CAAs. Furthermore, Runx1 expression was also increased in the peritumoral adipose tissue of both breast cancer mouse models and clinical patient samples. Overexpression of Runx1 in 3T3-L1 preadipocytes resulted in reduced adipocyte volume, decreased lipid droplet size, diminished expression of mature adipocyte markers, and an increase in pro-inflammatory factor levels. These findings suggest that Runx1 overexpression facilitates the transformation of adipocytes into CAAs, thereby enhancing breast cancer cell migration and invasion. Conversely, Runx1 knockdown in CAAs diminished their supportive role in cancer progression. Mechanically, Runx1 enhances breast cancer development by regulating perilipin 1 (Plin1) levels, the overexpression of Plin1 in adipocytes inhibited the effect of Runx1 to promote the transition of adipocytes into CAAs. Our findings propose that targeting Runx1 in CAAs may represent a novel therapeutic strategy for breast cancer intervention.