title: Immunohistochemical analysis of cancer stem cell markers in invasive breast carcinoma and associated ductal carcinoma in situ: relationships with markers of tumor hypoxia and microvascularity.
abstract: We performed immunohistochemical analysis of 3 cancer stem cell-related markers (CD44(+)/CD24(-/low), aldehyde dehydrogenase [ALDH]-1, CD133) in 94 invasive ductal carcinomas and assessed relationships with markers of hypoxia (carbonic anhydrase IX [CAIX]), tumor microvessel density (CD31), and clinicopathologic variables. Overall, 10% of tumors were CD44(+)/CD24(-/low), 13% were ALDH-1(+), 25% were CD133(+), 35% were immunonegative, and 1 tumor was immunopositive for all 3 markers. Associated ductal carcinoma in situ (DCIS) was present in 48% of tumors. Marker immunopositivity was detected in DCIS in 13% (CD44(+)/CD24(-/low)), 7% (ALDH-1(+)), and 32% (CD133(+)) of these tumors and was more likely present in DCIS when also detected in the invasive compartment (P = .03, P = .001, and P = .009, respectively). CD44(+)/CD24(-/low) cells were more common in progesterone receptor-negative tumors (P < .01), and ALDH-1(+) cells were more common in estrogen receptor-negative tumors (P < .01). CD133(+) cells were more common in patients younger than 50 years (P < .05) and in high grade (P < .01), localized (P < .05), and estrogen receptor-negative (P < .001), progesterone receptor-negative (P = .02), and triple-negative breast cancers (P < .001). CD44(+)/CD24(-/low) (P = .06) and CD133(+) (P = .02) tumor cells were more common in CAIX(+) versus CAIX(-) tumors, whereas ALDH-1(+) tumors had a higher mean microvessel density than did ALDH-1(-) tumors (P = .002). No significant relationships were observed between the markers studied and survival for 5 years. Our study demonstrated the presence of cancer stem cell marker-positive tumor cells in DCIS as well as invasive breast cancer and showed that CD44(+)/CD24(-/low) and CD133(+) cells were more frequently observed in hypoxic regions of tumor, whereas ALDH-1(+) cells more commonly colocalized to tumors with high microvessel density.
authors.affiliation: Department of Pathology, University of Otago, Christchurch, Christchurch 8140, New Zealand. margaret.currie@otago.ac.nz
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Currie
authors.forename: Brooke E
authors.initials: BE
authors.lastname: Beardsley
authors.forename: Gavin C
authors.initials: GC
authors.lastname: Harris
authors.forename: Sarah P
authors.initials: SP
authors.lastname: Gunningham
authors.forename: Gabi U
authors.initials: GU
authors.lastname: Dachs
authors.forename: Birgit
authors.initials: B
authors.lastname: Dijkstra
authors.forename: Helen R
authors.initials: HR
authors.lastname: Morrin
authors.forename: J Elisabeth
authors.initials: JE
authors.lastname: Wells
authors.forename: Bridget A
authors.initials: BA
authors.lastname: Robinson
mesh_terms: D000071916:AC133 Antigen; D000080924:Aldehyde Dehydrogenase 1 Family; D015703:Antigens, CD / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D051927:CD24 Antigen / Q000378:metabolism; D018270:Carcinoma, Ductal, Breast / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D000860:Hypoxia; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000378:metabolism; D055806:Microvessels; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000378:metabolism; D050697:Retinal Dehydrogenase / Q000378:metabolism; D012189:Retrospective Studies
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D014408:Biomarkers, Tumor; D051927:CD24 Antigen; C497889:CD24 protein, human; C497483:CD44 protein, human; D006023:Glycoproteins; D018960:Hyaluronan Receptors; D007527:Isoenzymes; C000606023:PROM1 protein, human; D010455:Peptides; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase