Activating Transcription Factor 4 Promotes Angiogenesis of Breast Cancer through Enhanced Macrophage Recruitment

Angiogenesis plays an important role in the progression of tumor. Besides being regulated by tumor cells per se, tumor angiogenesis is also influenced by stromal cells in tumor microenvironment (TME), for example, tumor associated macrophages (TAMs). Activating transcription factor 4 (ATF4), a member of the ATF/CREB family, has been reported to be related to tumor angiogenesis. In this study, we found that exogenous overexpression of ATF4 in mouse breast cancer cells promotes tumor growth via increasing tumor microvascular density. However, ATF4 overexpression failed to increase the expression level of a series of proangiogenic factors including vascular endothelial growth factor A (VEGFA) in tumor cells in this model. Thus, we further investigated the infiltration of proangiogenic macrophages in tumor tissues and found that ATF4-overexpressing tumors could recruit more macrophages via secretion of macrophage colony stimulating factor (M-CSF). Overall, we concluded that exogenous overexpression of ATF4 in breast cancer cells may facilitate the recruitment of macrophages into tumor tissues and promote tumor angiogenesis and tumor growth indirectly.

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miR-590–3p inhibits proliferation and promotes apoptosis by targeting activating transcription factor 3 in human breast cancer cells

Biochimie ◽

10.1016/j.biochi.2018.07.023 ◽

2018 ◽

Vol 154 ◽

pp. 10-18 ◽

Cited By ~ 18

Author(s):

M. Rohini ◽

M. Gokulnath ◽

P.J. Miranda ◽

N. Selvamurugan

Keyword(s):

Breast Cancer ◽

Transcription Factor ◽

Cancer Cells ◽

Human Breast Cancer ◽

Breast Cancer Cells ◽

Activating Transcription Factor 3 ◽

Human Breast Cancer Cells ◽

Human Breast ◽

Activating Transcription Factor ◽

Transcription Factor 3

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Activating Transcription Factor 4 Modulates TGFβ-Induced Aggressiveness in Triple-Negative Breast Cancer via SMAD2/3/4 and mTORC2 Signaling

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-17-3125 ◽

2018 ◽

Vol 24 (22) ◽

pp. 5697-5709 ◽

Cited By ~ 14

Author(s):

Adrián González-González ◽

Esperanza Muñoz-Muela ◽

Juan A. Marchal ◽

Francisca E. Cara ◽

Maria P. Molina ◽

...

Keyword(s):

Breast Cancer ◽

Transcription Factor ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Activating Transcription Factor 4 ◽

Activating Transcription Factor ◽

Transcription Factor 4

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Breast cancer–associated macrophages promote tumorigenesis by suppressing succinate dehydrogenase in tumor cells

Science Signaling ◽

10.1126/scisignal.aax4585 ◽

2020 ◽

Vol 13 (652) ◽

pp. eaax4585 ◽

Cited By ~ 1

Author(s):

Valentí Gómez ◽

Thomas R. Eykyn ◽

Rami Mustapha ◽

Fabián Flores-Borja ◽

Victoria Male ◽

...

Keyword(s):

Breast Cancer ◽

Transcription Factor ◽

Cancer Cells ◽

Succinate Dehydrogenase ◽

Tumor Cells ◽

Breast Cancer Cells ◽

Ex Vivo ◽

Metabolic Enzyme ◽

Metastatic Progression ◽

Anti Inflammatory

Tumor-associated macrophages (TAMs) can exist in pro- and anti-inflammatory states. Anti-inflammatory TAMs (also referred to as M2-polarized) generally suppress antitumor immune responses and enhance the metastatic progression of cancer. To explore the mechanisms behind this phenomenon, we isolated macrophages from mice and humans, polarized them ex vivo, and examined their functional interaction with breast cancer cells in culture and in mice. We found that anti-inflammatory TAMs promoted a metabolic state in breast cancer cells that supported various protumorigenic phenotypes. Anti-inflammatory TAMs secreted the cytokine TGF-β that, upon engagement of its receptors in breast cancer cells, suppressed the abundance of the transcription factor STAT1 and, consequently, decreased that of the metabolic enzyme succinate dehydrogenase (SDH) in the tumor cells. The decrease in SDH levels in tumor cells resulted in an accumulation of succinate, which enhanced the stability of the transcription factor HIF1α and reprogrammed cell metabolism to a glycolytic state. TAM depletion-repletion experiments in a 4T1 mouse model additionally revealed that anti-inflammatory macrophages promoted HIF-associated vascularization and expression of the immunosuppressive protein PD-L1 in tumors. The findings suggest that anti-inflammatory TAMs promote tumor-associated angiogenesis and immunosuppression by altering metabolism in breast cancer cells.

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