title: Pentraxin-3 is a PI3K signaling target that promotes stem cell-like traits in basal-like breast cancers.
abstract: Basal-like breast cancers (BLBCs) exhibit hyperactivation of the phosphoinositide 3-kinase (PI3K) signaling pathway because of the frequent mutational activation of thePIK3CAcatalytic subunit and the genetic loss of its negative regulators PTEN (phosphatase and tensin homolog) and INPP4B (inositol polyphosphate-4-phosphatase type II). However, PI3K inhibitors have had limited clinical efficacy in BLBC management because of compensatory amplification of PI3K downstream signaling loops. Therefore, identification of critical PI3K mediators is paramount to the development of effective BLBC therapeutics. Using transcriptomic analysis of activated PIK3CA-expressing BLBC cells, we identified the gene encoding the humoral pattern recognition molecule pentraxin-3 (PTX3) as a critical target of oncogenic PI3K signaling. We found that PTX3 abundance is stimulated, in part, through AKT- and nuclear factor κB (NF-κB)-dependent pathways and that presence of PTX3 is necessary for PI3K-induced stem cell-like traits. We further showed thatPTX3expression is greater in tumor samples from patients with BLBC and that it is prognostic of poor patient survival. Our results thus reveal PTX3 as a newly identified PI3K-regulated biomarker and a potential therapeutic target in BLBC.
authors.affiliation: Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Clémence
authors.identifier: 0000-0001-6662-755X
authors.initials: C
authors.lastname: Thomas
authors.affiliation: Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Whitney
authors.initials: W
authors.lastname: Henry
authors.affiliation: Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Benjamin G
authors.identifier: 0000-0002-9477-7317
authors.initials: BG
authors.lastname: Cuiffo
authors.affiliation: Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Anthony Y
authors.initials: AY
authors.lastname: Collmann
authors.affiliation: Institut Curie, Paris Cedex 05, France.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Marangoni
authors.affiliation: Institut Curie, Paris Cedex 05, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Benhamo
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Bhasin
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Cheng
authors.identifier: 0000-0002-7076-3666
authors.initials: C
authors.lastname: Fan
authors.affiliation: Institut Curie, Paris Cedex 05, France.
authors.forename: Laetitia
authors.identifier: 0000-0003-1755-6307
authors.initials: L
authors.lastname: Fuhrmann
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Albert S
authors.initials: AS
authors.lastname: Baldwin
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Charles
authors.identifier: 0000-0001-9827-2247
authors.initials: C
authors.lastname: Perou
authors.affiliation: Institut Curie, Paris Cedex 05, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Vincent-Salomon
authors.affiliation: Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Toker
authors.affiliation: Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. akarnoub@bidmc.harvard.edu.|Harvard Stem Cell Institute, Cambridge, MA 02138, USA.|Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
authors.forename: Antoine E
authors.identifier: 0000-0002-0634-7510
authors.initials: AE
authors.lastname: Karnoub
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D002097:C-Reactive Protein / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D040641:Quantitative Trait Loci; D000683:Serum Amyloid P-Component / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000099153:Pentraxins
chemical_list: D014408:Biomarkers, Tumor; D002097:C-Reactive Protein; D058534:Class I Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D051057:Proto-Oncogene Proteins c-akt; D000683:Serum Amyloid P-Component; D000099153:Pentraxins; C484760:PIK3CA protein, human; C053153:phosphatidylinositol-3,4-bisphosphate 4-phosphatase