. 2012 Aug; 18(9):534-43.
doi: 10.1016/j.molmed.2012.08.001.

Molecular mechanisms mediating metastasis of hypoxic breast cancer cells

Gregg L Semenza 1 
  • PMID: 22921864
  •     57 References
  •     91 citations


Breast cancers contain regions of intratumoral hypoxia in which reduced O(2) availability activates the hypoxia-inducible factors HIF-1 and HIF-2, which increase the transcription of genes encoding proteins that are required for many important steps in cancer progression. Recently, HIFs have been shown to play critical roles in the metastasis of breast cancer to the lungs through the transcriptional activation of genes encoding angiopoietin-like 4 and L1 cell adhesion molecule, which promote the extravasation of circulating cancer cells from the lung vasculature, and the lysyl oxidase family members LOX, LOXL2, and LOXL4, which promote invasion and metastatic niche formation. Digoxin, a drug that inhibits HIF-1 activity, blocks primary tumor growth, vascularization, invasion, and metastasis in ex vivo and in vivo assays.

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HIF-2α, acting via miR-191, is involved in angiogenesis and metastasis of arsenite-transformed HBE cells.
Wenchao Xu, Fei Luo, +9 authors, Aihua Zhang.
Toxicol Res (Camb), 2015 Nov 06; 5(1). PMID: 30090327    Free PMC article.
HIF-1α/Beclin1-Mediated Autophagy Is Involved in Neuroprotection Induced by Hypoxic Preconditioning.
Na Lu, Xingxing Li, +7 authors, Haixia Lu.
J Mol Neurosci, 2018 Sep 12; 66(2). PMID: 30203298    Free PMC article.
P2Y2R-mediated inflammasome activation is involved in tumor progression in breast cancer cells and in radiotherapy-resistant breast cancer.
Hana Jin, Young Shin Ko, Hye Jung Kim.
Int J Oncol, 2018 Sep 19; 53(5). PMID: 30226596    Free PMC article.
Fructose 2,6-Bisphosphate in Cancer Cell Metabolism.
Ramon Bartrons, Helga Simon-Molas, +4 authors, Ubaldo E Martinez-Outschoorn.
Front Oncol, 2018 Sep 21; 8. PMID: 30234009    Free PMC article.
Collagen prolyl 4-hydroxylase 1 is essential for HIF-1α stabilization and TNBC chemoresistance.
Gaofeng Xiong, Rachel L Stewart, +6 authors, Ren Xu.
Nat Commun, 2018 Oct 28; 9(1). PMID: 30367042    Free PMC article.
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Protective role of all-trans retinoic acid (ATRA) against hypoxia-induced malignant potential of non-invasive breast tumor derived cells.
Yasamin Al-Qassab, Silvia Grassilli, +3 authors, Valeria Bertagnolo.
BMC Cancer, 2018 Dec 01; 18(1). PMID: 30497437    Free PMC article.
A combined microfluidic-transcriptomic approach to characterize the extravasation potential of cancer cells.
Simone Bersini, Agnes Miermont, +4 authors, Giulia Adriani.
Oncotarget, 2018 Dec 14; 9(90). PMID: 30546831    Free PMC article.
MITF controls the TCA cycle to modulate the melanoma hypoxia response.
Pakavarin Louphrasitthiphol, Ioanna Ledaki, +6 authors, Colin R Goding.
Pigment Cell Melanoma Res, 2019 Jun 18; 32(6). PMID: 31207090    Free PMC article.
The interplay between HIF-1α and noncoding RNAs in cancer.
Xiafeng Peng, Han Gao, +3 authors, Chaoying Liu.
J Exp Clin Cancer Res, 2020 Feb 06; 39(1). PMID: 32014012    Free PMC article.
Fibronectin in Cancer: Friend or Foe.
Tsung-Cheng Lin, Cheng-Han Yang, +3 authors, Hung-Chi Cheng.
Cells, 2019 Dec 22; 9(1). PMID: 31861892    Free PMC article.
A SUMOylation-dependent HIF-1α/CLDN6 negative feedback mitigates hypoxia-induced breast cancer metastasis.
Yiyang Jia, Yantong Guo, +9 authors, Chengshi Quan.
J Exp Clin Cancer Res, 2020 Feb 26; 39(1). PMID: 32093760    Free PMC article.
Glutaminase 1 expression in colorectal cancer cells is induced by hypoxia and required for tumor growth, invasion, and metastatic colonization.
Lisha Xiang, Jun Mou, +5 authors, Ganfeng Xie.
Cell Death Dis, 2019 Jan 25; 10(2). PMID: 30674873    Free PMC article.
Downregulation of lysyl oxidase and lysyl oxidase-like protein 2 suppressed the migration and invasion of trophoblasts by activating the TGF-β/collagen pathway in preeclampsia.
Xiang-Hong Xu, Yuanhui Jia, +8 authors, Li-Ping Jin.
Exp Mol Med, 2019 Feb 26; 51(2). PMID: 30804321    Free PMC article.
Cardamonin inhibits breast cancer growth by repressing HIF-1α-dependent metabolic reprogramming.
Jinmei Jin, Shuiping Qiu, +9 authors, Xiaojun Wu.
J Exp Clin Cancer Res, 2019 Aug 29; 38(1). PMID: 31455352    Free PMC article.
Digoxin Enhances the Anticancer Effect on Non-Small Cell Lung Cancer While Reducing the Cardiotoxicity of Adriamycin.
Yingying Wang, Qian Ma, +8 authors, Dexin Kong.
Front Pharmacol, 2020 Mar 18; 11. PMID: 32180730    Free PMC article.
Lysyl oxidase induces epithelial-mesenchymal transition and predicts intrahepatic metastasis of hepatocellular carcinoma.
Naoki Umezaki, Shigeki Nakagawa, +10 authors, Hideo Baba.
Cancer Sci, 2019 Mar 29; 110(6). PMID: 30919528    Free PMC article.
Evaluation of Hypoxia-Inducible Factor-1 Alpha (HIF-1α) in Equine Sarcoid: An Immunohistochemical and Biochemical Study.
Manuela Martano, Gennaro Altamura, +4 authors, Paola Maiolino.
Pathogens, 2020 Jan 18; 9(1). PMID: 31947661    Free PMC article.
Basic Biology of Hypoxic Responses Mediated by the Transcription Factor HIFs and its Implication for Medicine.
Kiichi Hirota.
Biomedicines, 2020 Feb 20; 8(2). PMID: 32069878    Free PMC article.
Cyclooxygenase-2-prostaglandin E2-eicosanoid receptor inflammatory axis: a key player in Kaposi's sarcoma-associated herpes virus associated malignancies.
Arun George Paul, Bala Chandran, Neelam Sharma-Walia.
Transl Res, 2013 Apr 10; 162(2). PMID: 23567332    Free PMC article.
HIF-1α metabolically controls collagen synthesis and modification in chondrocytes.
Steve Stegen, Kjell Laperre, +16 authors, Geert Carmeliet.
Nature, 2019 Jan 18; 565(7740). PMID: 30651640    Free PMC article.
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Overexpression of HIF-1α protects PC12 cells against OGD/R-evoked injury by reducing miR-134 expression.
Hongliang Zhang, Xianming Liu, +2 authors, Wei Liu.
Cell Cycle, 2020 Apr 09; 19(9). PMID: 32266863    Free PMC article.
Antifibrotic therapy to normalize the tumor microenvironment.
Anette Hauge, Einar K Rofstad.
J Transl Med, 2020 May 22; 18(1). PMID: 32434573    Free PMC article.
Subtype-specific characterization of breast cancer invasion using a microfluidic tumor platform.
Hye-Ran Moon, Natalia Ospina-Muñoz, +4 authors, Bumsoo Han.
PLoS One, 2020 Jun 17; 15(6). PMID: 32544183    Free PMC article.
The Hypoxic Response Expression as a Survival Biomarkers in Treatment-Naive Advanced Breast Cancer.
Irwan Gunawan, Mochammad Hatta, Andi Fachruddin Benyamin, Andi Asadul Islam.
Asian Pac J Cancer Prev, 2020 Mar 28; 21(3). PMID: 32212787    Free PMC article.
ASC modulates HIF-1α stability and induces cell mobility in OSCC.
Chi-Sheng Wu, Ian Yi-Feng Chang, +5 authors, Yu-Sun Chang.
Cell Death Dis, 2020 Sep 05; 11(9). PMID: 32883954    Free PMC article.
Orchestration of lincRNA-p21 and miR-155 in Modulating the Adaptive Dynamics of HIF-1α.
Cheng-Yuan Sun, Xiao-Peng Zhang, Feng Liu, Wei Wang.
Front Genet, 2020 Sep 26; 11. PMID: 32973869    Free PMC article.
Extracellular Vesicles as Transmitters of Hypoxia Tolerance in Solid Cancers.
Marijke I Zonneveld, Tom G H Keulers, Kasper M A Rouschop.
Cancers (Basel), 2019 Feb 01; 11(2). PMID: 30699970    Free PMC article.
Potential monoamine oxidase A inhibitor suppressing paclitaxel-resistant non-small cell lung cancer metastasis and growth.
Xiaoguang Yang, Dongxue Zhao, +6 authors, Dun Wang.
Thorac Cancer, 2020 Sep 03; 11(10). PMID: 32875729    Free PMC article.
Depleting RhoA/Stress Fiber-Organized Fibronectin Matrices on Tumor Cells Non-Autonomously Aggravates Fibroblast-Driven Tumor Cell Growth.
Li-Tzu Huang, Chen-Lung Tsai, +4 authors, Hung-Chi Cheng.
Int J Mol Sci, 2020 Nov 08; 21(21). PMID: 33158289    Free PMC article.
Microvesicles derived from human bone marrow mesenchymal stem cells promote U2OS cell growth under hypoxia: the role of PI3K/AKT and HIF-1α.
Shanshan Lin, Bo Zhu, +2 authors, Chuhuai Wang.
Hum Cell, 2018 Dec 07; 32(1). PMID: 30506278
Inhibition of ATM reverses EMT and decreases metastatic potential of cisplatin-resistant lung cancer cells through JAK/STAT3/PD-L1 pathway.
Mingjing Shen, Zhonghua Xu, +5 authors, Yongbing Chen.
J Exp Clin Cancer Res, 2019 Apr 10; 38(1). PMID: 30961670    Free PMC article.
Microenvironmental Determinants of Breast Cancer Metastasis: Focus on the Crucial Interplay Between Estrogen and Insulin/Insulin-Like Growth Factor Signaling.
Veronica Vella, Ernestina Marianna De Francesco, +4 authors, Antonino Belfiore.
Front Cell Dev Biol, 2020 Dec 29; 8. PMID: 33364239    Free PMC article.
Mechanism for oral tumor cell lysyl oxidase like-2 in cancer development: synergy with PDGF-AB.
Faranak Mahjour, Vrinda Dambal, +4 authors, Philip C Trackman.
Oncogenesis, 2019 May 16; 8(5). PMID: 31086173    Free PMC article.
P4HA1 as an unfavorable prognostic marker promotes cell migration and invasion of glioblastoma via inducing EMT process under hypoxia microenvironment.
Xiaosan Zhu, Shanshan Liu, +3 authors, Tianhai Ji.
Am J Cancer Res, 2021 Feb 13; 11(2). PMID: 33575089    Free PMC article.
A Genome-Wide Analysis of the Gene Expression and Alternative Splicing Events in a Whole-Body Hypoxic Preconditioning Mouse Model.
Jun Li, Hongyu Zhao, +3 authors, Zuwei Yan.
Neurochem Res, 2021 Feb 15; 46(5). PMID: 33582968
Metabolite Profiling and Characterization of LW6, a Novel HIF-1α Inhibitor, as an Antitumor Drug Candidate in Mice.
Kiho Lee, Ji-Yoon Lee, +6 authors, Soo Jin Oh.
Molecules, 2021 Apr 04; 26(7). PMID: 33808438    Free PMC article.
E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones.
Tasuku Ishida, Alessio Ciulli.
SLAS Discov, 2020 Nov 05; 26(4). PMID: 33143537    Free PMC article.
Targeting the Tumor Core: Hypoxia-Responsive Nanoparticles for the Delivery of Chemotherapy to Pancreatic Tumors.
Matthew I Confeld, Babak Mamnoon, +8 authors, Sanku Mallik.
Mol Pharm, 2020 Jun 11; 17(8). PMID: 32521162    Free PMC article.
Targeting GLS1 to cancer therapy through glutamine metabolism.
Wei Yu, XiangYu Yang, +3 authors, YongJie Xin.
Clin Transl Oncol, 2021 May 24;. PMID: 34023970