Hypoxia/reoxygenation: a dynamic regulator of lysyl oxidase-facilitated breast cancer migration.
Fluctuating oxygen levels characterize the microenvironment of many cancers and tumor hypoxia is associated with increased invasion and metastatic potential concomitant with a poor prognosis. Similarly, the expression of lysyl oxidase (LOX) in breast cancer facilitates tumor cell migration and is associated with estrogen receptor negative status and reduced patient survival. Here we demonstrate that hypoxia/reoxygenation drives poorly invasive breast cancer cells toward a more aggressive phenotype by up-regulating LOX expression and catalytic activity. Specifically, hypoxia markedly increased LOX protein expression; however, catalytic activity (beta-aminopropionitrile inhibitable hydrogen peroxide production) was significantly reduced under hypoxic conditions. Moreover, poorly invasive breast cancer cells displayed a marked increase in LOX-dependent FAK/Src activation and cell migration following hypoxia/reoxygenation, but not in response to hypoxia alone. Furthermore, LOX expression is only partially dependent on hypoxia inducible factor-1 (HIF-1alpha) in poorly invasive breast cancer cells, as hypoxia mimetics and overexpression of HIF-1alpha could not up-regulate LOX expression to the levels observed under hypoxia. Clinically, LOX expression positively correlates with tumor progression and co-localization with hypoxic regions (defined by HIF-1alpha expression) in ductal carcinoma in situ and invasive ductal carcinoma primary tumors. However, positive correlation is lost in metastatic tumors, suggesting that LOX expression is independent of a hypoxic environment at later stages of tumor progression. This work demonstrates that both hypoxia and reoxygenation are necessary for LOX catalytic activity which facilitates breast cancer cell migration through a hydrogen peroxide-mediated mechanism; thereby illuminating a potentially novel mechanism by which poorly invasive cancer cells can obtain metastatic competency.
Children's Memorial Research Center, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine at Northwestern University, Chicago, Illinois 60614, USA.
Lynne-Marie
LM
Postovit
Daniel E
DE
Abbott
Stacey L
SL
Payne
William W
WW
Wheaton
Naira V
NV
Margaryan
Richard
R
Sullivan
Matthias K
MK
Jansen
Katalin
K
Csiszar
Mary J C
MJ
Hendrix
Dawn A
DA
Kirschmann
D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D008249:Protein-Lysine 6-Oxidase / Q000096:biosynthesis* / Q000235:genetics
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D006861:Hydrogen Peroxide; D008249:Protein-Lysine 6-Oxidase