title: The JAK2/STAT3 signaling pathway is required for growth of CD44⁺CD24⁻ stem cell-like breast cancer cells in human tumors.
abstract: Intratumor heterogeneity is a major clinical problem because tumor cell subtypes display variable sensitivity to therapeutics and may play different roles in progression. We previously characterized 2 cell populations in human breast tumors with distinct properties: CD44+CD24- cells that have stem cell-like characteristics, and CD44-CD24+ cells that resemble more differentiated breast cancer cells. Here we identified 15 genes required for cell growth or proliferation in CD44+CD24- human breast cancer cells in a large-scale loss-of-function screen and found that inhibition of several of these (IL6, PTGIS, HAS1, CXCL3, and PFKFB3) reduced Stat3 activation. We found that the IL-6/JAK2/Stat3 pathway was preferentially active in CD44+CD24- breast cancer cells compared with other tumor cell types, and inhibition of JAK2 decreased their number and blocked growth of xenografts. Our results highlight the differences between distinct breast cancer cell types and identify targets such as JAK2 and Stat3 that may lead to more specific and effective breast cancer therapies.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Lauren L C
authors.initials: LL
authors.lastname: Marotta
authors.forename: Vanessa
authors.initials: V
authors.lastname: Almendro
authors.forename: Andriy
authors.initials: A
authors.lastname: Marusyk
authors.forename: Michail
authors.initials: M
authors.lastname: Shipitsin
authors.forename: Janina
authors.initials: J
authors.lastname: Schemme
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Walker
authors.forename: Noga
authors.initials: N
authors.lastname: Bloushtain-Qimron
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Kim
authors.forename: Sibgat A
authors.initials: SA
authors.lastname: Choudhury
authors.forename: Reo
authors.initials: R
authors.lastname: Maruyama
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Wu
authors.forename: Mithat
authors.initials: M
authors.lastname: Gönen
authors.forename: Laura A
authors.initials: LA
authors.lastname: Mulvey
authors.forename: Marina O
authors.initials: MO
authors.lastname: Bessarabova
authors.forename: Sung Jin
authors.initials: SJ
authors.lastname: Huh
authors.forename: Serena J
authors.initials: SJ
authors.lastname: Silver
authors.forename: So Young
authors.initials: SY
authors.lastname: Kim
authors.forename: So Yeon
authors.initials: SY
authors.lastname: Park
authors.forename: Hee Eun
authors.initials: HE
authors.lastname: Lee
authors.forename: Karen S
authors.initials: KS
authors.lastname: Anderson
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Richardson
authors.forename: Tatiana
authors.initials: T
authors.lastname: Nikolskaya
authors.forename: Yuri
authors.initials: Y
authors.lastname: Nikolsky
authors.forename: X Shirley
authors.initials: XS
authors.lastname: Liu
authors.forename: David E
authors.initials: DE
authors.lastname: Root
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.forename: David A
authors.initials: DA
authors.lastname: Frank
authors.forename: Kornelia
authors.initials: K
authors.lastname: Polyak
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051927:CD24 Antigen / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D014183:Transplantation, Heterologous
chemical_list: D051927:CD24 Antigen; D018960:Hyaluronan Receptors; D015850:Interleukin-6; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D053614:Janus Kinase 2