title: Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors.
abstract: Carbonic anhydrase IX (CAIX) is a hypoxia and HIF-1-inducible protein that regulates intra- and extracellular pH under hypoxic conditions and promotes tumor cell survival and invasion in hypoxic microenvironments. Interrogation of 3,630 human breast cancers provided definitive evidence of CAIX as an independent poor prognostic biomarker for distant metastases and survival. shRNA-mediated depletion of CAIX expression in 4T1 mouse metastatic breast cancer cells capable of inducing CAIX in hypoxia resulted in regression of orthotopic mammary tumors and inhibition of spontaneous lung metastasis formation. Stable depletion of CAIX in MDA-MB-231 human breast cancer xenografts also resulted in attenuation of primary tumor growth. CAIX depletion in the 4T1 cells led to caspase-independent cell death and reversal of extracellular acidosis under hypoxic conditions in vitro. Treatment of mice harboring CAIX-positive 4T1 mammary tumors with novel CAIX-specific small molecule inhibitors that mimicked the effects of CAIX depletion in vitro resulted in significant inhibition of tumor growth and metastasis formation in both spontaneous and experimental models of metastasis, without inhibitory effects on CAIX-negative tumors. Similar inhibitory effects on primary tumor growth were observed in mice harboring orthotopic tumors comprised of lung metatstatic MDA-MB-231 LM2-4(Luc+) cells. Our findings show that CAIX is vital for growth and metastasis of hypoxic breast tumors and is a specific, targetable biomarker for breast cancer metastasis.
authors.affiliation: Department of Integrative Oncology, BC Cancer Agency, British Columbia, Canada.
authors.forename: Yuanmei
authors.initials: Y
authors.lastname: Lou
authors.forename: Paul C
authors.initials: PC
authors.lastname: McDonald
authors.forename: Arusha
authors.initials: A
authors.lastname: Oloumi
authors.forename: Stephen
authors.initials: S
authors.lastname: Chia
authors.forename: Christina
authors.initials: C
authors.lastname: Ostlund
authors.forename: Ardalan
authors.initials: A
authors.lastname: Ahmadi
authors.forename: Alastair
authors.initials: A
authors.lastname: Kyle
authors.forename: Ulrich
authors.initials: U
authors.lastname: Auf dem Keller
authors.forename: Samuel
authors.initials: S
authors.lastname: Leung
authors.forename: David
authors.initials: D
authors.lastname: Huntsman
authors.forename: Blaise
authors.initials: B
authors.lastname: Clarke
authors.forename: Brent W
authors.initials: BW
authors.lastname: Sutherland
authors.forename: Dawn
authors.initials: D
authors.lastname: Waterhouse
authors.forename: Marcel
authors.initials: M
authors.lastname: Bally
authors.forename: Calvin
authors.initials: C
authors.lastname: Roskelley
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Overall
authors.forename: Andrew
authors.initials: A
authors.lastname: Minchinton
authors.forename: Fabio
authors.initials: F
authors.lastname: Pacchiano
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Carta
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Nadia
authors.initials: N
authors.lastname: Touisni
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Winum
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.forename: Shoukat
authors.initials: S
authors.lastname: Dedhar
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000096:biosynthesis / Q000172:deficiency / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D002257:Carbonic Anhydrase Inhibitors; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; C492796:Car9 protein, mouse