A novel HMGA1-CCNE2-YAP axis regulates breast cancer aggressiveness

Abstract

High Mobility Group A1 (HMGA1) is an architectural chromatin factor that promotes neoplastic transformation and progression. However, the mechanism by which HMGA1 exerts its oncogenic function is not fully understood. Here, we show that cyclin E2 (CCNE2) acts downstream of HMGA1 to regulate the motility and invasiveness of basal-like breast cancer cells by promoting the nuclear localization and activity of YAP, the downstream mediator of the Hippo pathway. Mechanistically, the activity of MST1/2 and LATS1/2, the core kinases of the Hippo pathway, are required for the HMGA1- and CCNE2-mediated regulation of YAP localization. In breast cancer patients, high levels of HMGA1 and CCNE2 expression are associated with the YAP/TAZ signature, supporting this connection. Moreover, we provide evidence that CDK inhibitors induce the translocation of YAP from the nucleus to the cytoplasm, resulting in a decrease in its activity. These findings reveal an association between HMGA1 and the Hippo pathway that is relevant to stem cell biology, tissue homeostasis, and cancer.

HMGA1 Overexpression is Associated With the Malignant Status and Progression of Breast Cancer

“…Previous studies have reported that HMGA1 plays a significant role in cell proliferation and migration through the induction of the epithelial‐mesenchymal transition and pluripotent stem cells (Shah et al, ). Pegoraro et al () also showed that HMGA1 can regulate breast cancer progression through activating migration‐ and invasion‐associated genes, such as the CCNE2‐YAP axis and Notch and Pin1/mutant p53 signaling pathways.…”

“…High mobility group A1 (HMGA1), a member of the HMGA family, is highly expressed during embryogenesis (Pegoraro et al, ), while HMGA1 protein expression levels are low or undetectable in normal adult tissues (Zhou et al, ; van't Veer et al, ). Studies have shown that HMGA1 plays an important role in several types of cancers, such as breast cancer (Cianfrocca et al, ), colorectal cancer (Williama et al, ), pancreatic cancer (Piscuoglio et al, ), prostate cancer (Zhang et al, ), ovarian cancer (Liu et al, ), and lung cancer (Lin et al, ).…”

Gene expression profiling of the 8q22-24 position in human breast cancer: TSPYL5, MTDH, ATAD2 and CCNE2 genes are implicated in oncogenesis, while WISP1 and EXT1 genes may predict a risk of metastasis

“…It has been demonstrated to have a significant role in the pathogenesis and invasiveness of breast cancer (25,45). By way of example, Li et al (45) reported that the CCNE2 gene is overexpressed, simultaneously with c-Myc, in human breast cancer, and potentially acts as a promoter for development of the disease.…”

“…The TSPYL5 gene has been suggested to have a causative role in breast tumorigenesis (24). The CCNE2 gene has been demonstrated to have a role in the invasiveness of breast cancer cells (25). To the best of our knowledge, there have been no investigations into the role of EXT1 in the pathogenesis of breast carcinoma.…”

YAP enhances the pro‐proliferative transcriptional activity of mutant p53 proteins

“…YAP1 is an oncogene, amplified or hyperactivated in a number of human solid tumors. It is considered the main effector of the Hippo tumor suppressor pathway [20][21][22][23]. Notably, YAP and mutant p53 proteins physically interact and can be concomitantly found on the consensus sequences recognized and bound to the heterotrimeric transcription factor NF-Y.…”