HMGA1: A Master Regulator of Tumor Progression in Triple-Negative Breast Cancer Cells

Abstract

Emerging evidence suggests that tumor cells metastasize by co-opting stem cell transcriptional networks, although the molecular underpinnings of this process are poorly understood. Here, we show for the first time that the high mobility group A1 (HMGA1) gene drives metastatic progression in triple negative breast cancer cells (MDA-MB-231, Hs578T) by reprogramming cancer cells to a stem-like state. Silencing HMGA1 expression in invasive, aggressive breast cancer cells dramatically halts cell growth and results in striking morphologic changes from mesenchymal-like, spindle-shaped cells to cuboidal, epithelial-like cells. Mesenchymal genes (Vimentin, Snail) are repressed, while E-cadherin is induced in the knock-down cells. Silencing HMGA1 also blocks oncogenic properties, including proliferation, migration, invasion, and orthotopic tumorigenesis. Metastatic progression following mammary implantation is almost completely abrogated in the HMGA1 knock-down cells. Moreover, silencing HMGA1 inhibits the stem cell property of three-dimensional mammosphere formation, including primary, secondary, and tertiary spheres. In addition, knock-down of HMGA1 depletes cancer initiator/cancer stem cells and prevents tumorigenesis at limiting dilutions. We also discovered an HMGA1 signature in triple negative breast cancer cells that is highly enriched in embryonic stem cells. Together, these findings indicate that HMGA1 is a master regulator of tumor progression in breast cancer by reprogramming cancer cells through stem cell transcriptional networks. Future studies are needed to determine how to target HMGA1 in therapy.

MiR-142-3p Functions as a Potential Tumor Suppressor in Human Osteosarcoma by Targeting HMGA1

“…HMGA1 is necessary for tumor-promoter-induced transformation and enhances tumor growth and invasion, which is opposite of the role of miR-142-3p [24,25,26,27,28]. Conversely, silencing of HMGA1 has been demonstrated to suppress tumor cell proliferation and invasion [29]. In this study, we identified HMGA1 as a functional target of miR-142-3p.…”

Overexpression of HMGA1 correlates with the malignant status and prognosis of breast cancer

“…In basal-like breast cancer subtype, Pegoraro et al indicated that HMGA1 was fundamental in sustaining stem cell and metastatic properties through cooperating with the Wnt/beta-catenin and Pin1/mutant p53 signaling pathways [14]. Moreover, Shah et al reported that HMGA1 is a master regulator of tumor progression in breast cancer by reprogramming cancer cells through stem cell transcriptional networks in triple-negative breast cancer cells [15]. As for HMGA1 expression in breast cancer, most studies published so far have been performed on cell lines.…”

“…Moreover, HMGA1 is fundamental in sustaining stem cell and metastatic properties through cooperating with the Wnt/beta-catenin and Pin1/mutant p53 signaling pathways in basal-like breast cancer subtype [14]. In triple-negative breast cancer cells, HMGA1 is a master regulator of tumor progression in breast cancer by reprogramming cancer cells through stem cell transcriptional networks [15]. Although associations between HMGA1 expression and clinicopathological features including prognosis have been investigated in various human cancer such as lung cancer [16], colorectal cancer [17], liver cancer [18], pancreatic adenocarcinoma [19][20][21], and uveal melanomas [22], little is known about HMGA1 in breast cancer patients.…”

IBRUTinib: BRUTe force against bortezomib-resistant myeloma cells

“…3 Emerging evidence suggests that master regulators, such as the high mobility group A1 (HMGA1) chromatin remodeling protein, orchestrates the assembly of Nuclear-factor kappa B (NF-kB) and transcription factor complexes to induce stem cell transcriptional networks and downstream signaling pathways that maintain CSCs. [3][4][5][6] Prior studies also suggest that Nuclear-factor kappa B (NF-kB) is hyperactive in MM and leukemic stem cells (Fig. 1).…”