TGF-β1 induces HMGA1 expression in human breast cancer cells: Implications of the involvement of HMGA1 in TGF-β signaling

Abstract

Transforming growth factor-β1 (TGF-β1) signaling and high mobility group A (HMGA1) are known to play essential roles in the progression of breast cancer by inducing epithelial-mesenchymal transition. However, the correlation between TGF-β1 and HMGA1 in breast cancer cell is not yet well understood. In this study, we determined the effects of TGF-β1 on HMGA1 expression in breast cancer cells and examined the role of HMGA1 in breast cancer progression. Our results demonstrated that TGF-β1 induced the expression of HMGA1 in both MCF-7 and MDA-MB-231 breast cancer cells, as shown by RT-qPCR and immunofluorescence staining; however, the TGF-β1-induced expression of HMGA was blocked by treatment of the cells with phosphatidylinositol-3 kinase (PI3K) signaling inhibitors. Moreover, the HMGA1 promoter activity was found to be activated by TGF-β1 in the MCF-7 and MDA-MB-231 cells and we found that specificity protein 1 (Sp1) was involved in the TGF-β1-induced HMGA1 promoter activity, as shown by luciferase activity assay. Furthermore, the enforced expression of HMGA1 by transfection with a HMGA1 promoter enhanced cellular oncogenic properties, including proliferation, migration and invasion, and a tissue microarray revealed that breast tumors expressing human epidermal growth factor receptor 2 (HER2) showed higher expression levels of HMGA1 (P=0.007). In addition, higher HMGA1 expression levels were also observed in the ductal breast cancer cases compared with the lobular breast cancer cases (P=0.000). These findings establish the first link between HMGA1 and TGF-β1 in breast cancer, providing further evidence of the pivotal role of HMGA1 in breast cancer progression.

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

“…In this study, we also found that HMGA1 knockdown inhibited breast cancer cell proliferation using MTT and colony formation assays. Further results showed that HMGA1 knockdown also suppressed breast cancer cell migration, which is consistent with the previous study (Zu et al, ). Zu et al () demonstrated that HMGA1 could promote breast cancer cell proliferation and migration primarily through the phosphatidylinositol 3‐kinase (PI3K) signaling pathway.…”

“…Further results showed that HMGA1 knockdown also suppressed breast cancer cell migration, which is consistent with the previous study (Zu et al, ). Zu et al () demonstrated that HMGA1 could promote breast cancer cell proliferation and migration primarily through the phosphatidylinositol 3‐kinase (PI3K) signaling pathway. Furthermore, transforming growth factor‐β1 (TGF‐β1) could increase the expression of HMGA1 in both MDA‐MB‐231 and MCF‐7 breast cancer cells.…”

miR‐214 activates TP53 but suppresses the expression of RELA, CTNNB1, and STAT3 in human cervical and colorectal cancer cells

“…HMGA1 helps promote protumourigenic phenomena like proliferation, migration, and invasion in multiple ways: it activates the Akt/MMP9 cascade in pancreatic adenocarcinoma, HMGA1/MMP2 pathway in uterine carcinosarcomas, and blocks the expression of metastasis suppressor protein 1 in T‐cell leukaemia . Further, HMGA1 expression has been found to be induced by transforming growth factor beta (TGF‐β) signalling through specificity protein 1 and phosphatidyl inositol‐3 kinase, resulting in enhanced tumourigenic properties in breast carcinoma . High Mobility Group AT‐hook 1 could arguably act downstream of the sonic hedgehog pathway to inactivate the tumour suppressor parafibromin (mutated hyperthyroidism jaw‐tumour 2) resulting in aberrant cell‐cycle progress .…”

“…High Mobility Group AT‐hook 1 could arguably act downstream of the sonic hedgehog pathway to inactivate the tumour suppressor parafibromin (mutated hyperthyroidism jaw‐tumour 2) resulting in aberrant cell‐cycle progress . In breast carcinoma, HMGA1 is crucial to activation of several signalling pathways like Wnt, Notch, and Pin1‐dependent; TGF‐β/specificity protein 1/phosphatidyl inositol‐3 kinase; and Ras/extracellular signal‐regulated kinase (ERK) signalling pathways, which consequently boosts EMT. Specifically, the Notch signalling intermediates, JAG1 and HES1, and the Wnt‐effector, CTNNB1, mediate cross‐talk through HMGA1 to utilize the cell cycle promoter, Dishevelled‐EGL‐10‐Pleckstrin domain containing protein 1 (DEPDC1) to sustain EMT in basal‐like breast cancer cells.…”

“…32 Further, HMGA1 expression has been found to be induced by transforming growth factor beta (TGF-β) signalling through specificity protein 1 and phosphatidyl inositol-3 kinase, resulting in enhanced tumourigenic properties in breast carcinoma. 33 High Mobility Group AT-hook 1 could arguably act downstream of the sonic hedgehog pathway to inactivate the tumour suppressor parafibromin (mutated hyperthyroidism jaw-tumour 2) resulting in aberrant cell-cycle progress. 34 In breast carcinoma, HMGA1 is crucial to activation of several signalling pathways like Wnt, Notch, and Pin1-dependent 35 ; TGF-β/specificity protein 1/ phosphatidyl inositol-3 kinase 33 ; and Ras/extracellular signal-regulated kinase (ERK) 36 HPV-reinfected human cervical cancer cells.…”