Clinical Implications of Extracellular HMGA1 in Breast Cancer

Méndez, Olga; Pérez, Jose; Soberino, Jesús; Racca, Fabricio; Cortés, Javier; Villanueva, Josep

doi:10.3390/ijms20235950

Cited by 22 publications

(16 citation statements)

References 125 publications

(144 reference statements)

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“…However, patients with TNBC, hardly benefit from endocrine therapy or HER2 target therapy due to a lack of drug targets. TNBC accounts for 10-15% of all newly diagnosed breast cancer and is more prone to relapse (3). Most of the triple-negative breast cancers (TNBCs) develop originally and rapidly invade at early stage (4).…”

Section: Introductionmentioning

confidence: 99%

ESM1 promotes triple-negative breast cancer cell proliferation through activating AKT/NF-κB/Cyclin D1 pathway

Liu

Yang

et al. 2021

Ann Transl Med

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Background: Triple-negative breast cancer (TNBC) is a subtype of invasive breast cancer that tests negative for PR, ER and excess HER2 protein. TNBC has a greater progression potential with poorer prognosis, compared with other types of breast cancer. Endothelial cell-specific molecule 1 (ESM1), also known as endocan, is overexpressed in various cancers including breast cancer and may play an important role in cancer progression. Methods: The online resource of The Cancer Genome Atlas (TCGA) was used for analyzing the expression alteration of ESM1 in breast cancer patient tissues. We examined the changes of various malignant behaviors of TNBC cell and in vivo tumor growth after inhibiting or overexpressing ESM1 in two human TNBC cell lines, MDA-MB-468 and MDA-MB-231. When ESM1 was knocked down or overexpressed in TNBC cell, AKT and p65 phosphorylation and Cyclin D1 expression were analyzed by western blotting. The ESM1overexpressing TNBC cell was treated with MK-2206 and BAY-117082 at various concentrations.Results: Our analyses show that ESM1 is overexpressed in TNBC cell lines as well as patient tissues, which is correlated to poor prognosis. Our results demonstrate that ESM1 knockdown decreases while overexpression of ESM1 increases in vitro proliferation, migration and invasion of TNBC cell and knockdown of ESM1 inhibits in vivo TNBC tumor growth. Our mechanistic study further discloses that ESM1 promotes the proliferation of TNBC cell through activating an Akt-dependent NF-κB/Cyclin D1 pathway.Conclusions: Our results demonstrate that ESM1 knockdown decreases while overexpression of ESM1 increases in vitro migration, proliferation and invasion of TNBC cell and knockdown of ESM1 inhibits in vivo tumor growth of TNBC in the xenograft mouse model. Our mechanistic study further discloses that ESM1 promotes the proliferation of TNBC cell through activating the Akt-dependent NF-κB/ CyclinD1 pathway. Our findings expand the knowledge about the molecular mechanisms underlying TNBC progression and provide rationale for using ESM1 as a therapeutic target or prognostic marker for TNBC.

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Section: Introductionmentioning

confidence: 99%

ESM1 promotes triple-negative breast cancer cell proliferation through activating AKT/NF-κB/Cyclin D1 pathway

Liu

Yang

et al. 2021

Ann Transl Med

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“…The unconventional secretion of HMGA1 warrants further study since this location provides an exciting avenue for therapeutic targeting. If secreted HMGA1 is a common feature in settings beyond TNBC cells, this could have important implications in cancer biology [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

HMGA1, Moonlighting Protein Function, and Cellular Real Estate: Location, Location, Location!

Pujals¹,

Resar

Villanueva

2021

Biomolecules

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The gene encoding the High Mobility Group A1 (HMGA1) chromatin remodeling protein is upregulated in diverse cancers where high levels portend adverse clinical outcomes. Until recently, HMGA1 was assumed to be a nuclear protein exerting its role in cancer by transcriptionally modulating gene expression and downstream signaling pathways. However, the discovery of an extracellular HMGA1-RAGE autocrine loop in invasive triple-negative breast cancer (TNBC) cell lines implicates HMGA1 as a “moonlighting protein” with different functions depending upon cellular location. Here, we review the role of HMGA1, not only as a chromatin regulator in cancer and stem cells, but also as a potential secreted factor that drives tumor progression. Prior work found that HMGA1 is secreted from TNBC cell lines where it signals through the receptor for advanced glycation end products (RAGE) to foster phenotypes involved in tumor invasion and metastatic progression. Studies in primary TNBC tumors also suggest that HMGA1 secretion associates with distant metastasis in TNBC. Given the therapeutic potential to target extracellular proteins, further work to confirm this role in other contexts is warranted. Indeed, crosstalk between nuclear and secreted HMGA1 could change our understanding of tumor development and reveal novel therapeutic opportunities relevant to diverse human cancers overexpressing HMGA1.

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“…In addition to the direct pro-survival signals delivered by RAGE in cancer cells, RAGE propagates and sustains pro-tumor host inflammatory responses [ 342 ]. HMGA1 and HMGB1 binding to RAGE promotes migration, invasion and metastasis of cancer cells [ 127 , 355 , 356 , 357 , 358 ]. The interaction of RAGE with its ligand HMGB1 induces epithelial-mesenchymal transition (EMT) of cancer cells [ 359 , 360 ].…”

Section: Pro-tumor Function Of Ragementioning

confidence: 99%

Leveling Up the Controversial Role of Neutrophils in Cancer: When the Complexity Becomes Entangled

Sionov

2021

Cells

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Neutrophils are the most abundant immune cell in the circulation of human and act as gatekeepers to discard foreign elements that have entered the body. They are essential in initiating immune responses for eliminating invaders, such as microorganisms and alien particles, as well as to act as immune surveyors of cancer cells, especially during the initial stages of carcinogenesis and for eliminating single metastatic cells in the circulation and in the premetastatic organs. Since neutrophils can secrete a whole range of factors stored in their many granules as well as produce reactive oxygen and nitrogen species upon stimulation, neutrophils may directly or indirectly affect carcinogenesis in both the positive and negative directions. An intricate crosstalk between tumor cells, neutrophils, other immune cells and stromal cells in the microenvironment modulates neutrophil function resulting in both anti- and pro-tumor activities. Both the anti-tumor and pro-tumor activities require chemoattraction towards the tumor cells, neutrophil activation and ROS production. Divergence is seen in other neutrophil properties, including differential secretory repertoire and membrane receptor display. Many of the direct effects of neutrophils on tumor growth and metastases are dependent on tight neutrophil–tumor cell interactions. Among them, the neutrophil Mac-1 interaction with tumor ICAM-1 and the neutrophil L-selectin interaction with tumor-cell sialomucins were found to be involved in the neutrophil-mediated capturing of circulating tumor cells resulting in increased metastatic seeding. On the other hand, the anti-tumor function of neutrophils was found to rely on the interaction between tumor-surface-expressed receptor for advanced glycation end products (RAGE) and Cathepsin G expressed on the neutrophil surface. Intriguingly, these two molecules are also involved in the promotion of tumor growth and metastases. RAGE is upregulated during early inflammation-induced carcinogenesis and was found to be important for sustaining tumor growth and homing at metastatic sites. Cathepsin G was found to be essential for neutrophil-supported lung colonization of cancer cells. These data level up the complexity of the dual role of neutrophils in cancer.

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Clinical Implications of Extracellular HMGA1 in Breast Cancer

Cited by 22 publications

References 125 publications

ESM1 promotes triple-negative breast cancer cell proliferation through activating AKT/NF-κB/Cyclin D1 pathway

ESM1 promotes triple-negative breast cancer cell proliferation through activating AKT/NF-κB/Cyclin D1 pathway

HMGA1, Moonlighting Protein Function, and Cellular Real Estate: Location, Location, Location!

Leveling Up the Controversial Role of Neutrophils in Cancer: When the Complexity Becomes Entangled

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