title: Hyperactivated mTOR and JAK2/STAT3 Pathways: Molecular Drivers and Potential Therapeutic Targets of Inflammatory and Invasive Ductal Breast Cancers After Neoadjuvant Chemotherapy.
abstract: BACKGROUND
  Inflammatory breast cancer (IBC) is an aggressive and rare cancer with a poor prognosis and a need for novel targeted therapeutic strategies. Preclinical IBC data showed strong activation of the phosphatidylinositide-3-kinase/mammalian target of rapamycin (mTOR) and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways, and expression of inflammatory cytokines and tumor-associated macrophages (TAMs).
  
  
  METHODS
  Archival tumor tissue from 3 disease types (IBC treated with neoadjuvant chemotherapy [NAC], n = 45; invasive ductal carcinoma [IDC] treated with NAC [n = 24; 'treated IDC'; and untreated IDC [n = 27; 'untreated IDC']) was analyzed for the expression of biomarkers phospho-S6 (pS6) (mTOR), phospho-JAK2 (pJAK2), pSTAT3, interleukin (IL)-6, CD68 (monocytes, macrophages), and CD163 (TAMs). Surrounding nontumor tissue was also analyzed.
  
  
  RESULTS
  Biomarker levels and surrogate activity according to site-specific phosphorylation were shown in the tumor tissue of all 3 disease types but were greatest in IBC and treated IDC and least in untreated IDC for pS6, pJAK2, pSTAT3, and IL-6. Of 37 IBC patients with complete biomarker data available, 100% were pS6-positive and 95% were pJAK2-positive. In nontumor tissue, biomarker levels were observed in all groups but were generally greatest in untreated IDC and least in IBC, except for JAK2.
  
  
  CONCLUSIONS
  IBC and treated IDC display similar levels of mTOR and JAK2 biomarker activation, which suggests a potential mechanism of resistance after NAC. Biomarker levels in surrounding nontumor tissue suggested that the stroma might be activated by chemotherapy and resembles the oncogenic tumor-promoting environment. Activation of pS6 and pJAK2 in IBC might support dual targeting of the mTOR and JAK/STAT pathways, and the need for prospective studies to investigate combined targeted therapies in IBC.
authors.affiliation: Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY. Electronic address: jhaverik@mskcc.org.
authors.forename: Komal
authors.initials: K
authors.lastname: Jhaveri
authors.affiliation: Division of Hematology & Medical Oncology, Department of Medicine, New York University School of Medicine, New York, NY.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Teplinsky
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY.
authors.forename: Deborah
authors.initials: D
authors.lastname: Silvera
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY.
authors.forename: Amanda
authors.initials: A
authors.lastname: Valeta-Magara
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY.
authors.forename: Rezina
authors.initials: R
authors.lastname: Arju
authors.affiliation: Department of Pathology, The Brooklyn Hospital Center, Brooklyn, NY.
authors.forename: Shah
authors.initials: S
authors.lastname: Giashuddin
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY.
authors.forename: Yasmeen
authors.initials: Y
authors.lastname: Sarfraz
authors.affiliation: Department of Pathology, The Brooklyn Hospital Center, Brooklyn, NY.
authors.forename: Melissa
authors.initials: M
authors.lastname: Alexander
authors.affiliation: Department of Pathology, The Brooklyn Hospital Center, Brooklyn, NY.
authors.forename: Farbod
authors.initials: F
authors.lastname: Darvishian
authors.affiliation: Department of Epidemiology and Biostatistics, George Washington University, Washington, DC.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Levine
authors.affiliation: Division of Biostatistics, New York University School of Medicine, New York, NY.
authors.forename: Salman
authors.initials: S
authors.lastname: Hashmi
authors.affiliation: Division of Biostatistics, New York University School of Medicine, New York, NY.
authors.forename: Ladan
authors.initials: L
authors.lastname: Zolfaghari
authors.affiliation: Division of Biostatistics, New York University School of Medicine, New York, NY.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Hoffman
authors.affiliation: Department of Epidemiology and Biostatistics, George Washington University, Washington, DC.
authors.forename: Baljit
authors.initials: B
authors.lastname: Singh
authors.affiliation: Division of Biostatistics, New York University School of Medicine, New York, NY.
authors.forename: Judith D
authors.initials: JD
authors.lastname: Goldberg
authors.affiliation: Division of Biostatistics, New York University School of Medicine, New York, NY.
authors.forename: Tsivia
authors.initials: T
authors.lastname: Hochman
authors.affiliation: Department of Radiation Oncology, Weill Cornell Medical College, New York, NY.
authors.forename: Silvia
authors.initials: S
authors.lastname: Formenti
authors.affiliation: Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Esteva
authors.affiliation: Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT.
authors.forename: Meena S
authors.initials: MS
authors.lastname: Moran
authors.affiliation: Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY; Department of Microbiology, New York University School of Medicine, New York, NY.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schneider
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D058922:Inflammatory Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D053614:Janus Kinase 2 / Q000378:metabolism*; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D053614:Janus Kinase 2; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D050796:STAT3 Transcription Factor; D058570:TOR Serine-Threonine Kinases; C494086:STAT3 protein, human; C546842:MTOR protein, human; C508053:ERBB2 protein, human; C507924:JAK2 protein, human
keywords: Biomarkers; Inflammatory breast cancer; Resistance to chemotherapy; Signaling pathways; Targeted therapies