Hyperactivated mTOR and JAK2/STAT3 Pathways: Molecular Drivers and Potential Therapeutic Targets of Inflammatory and Invasive Ductal Breast Cancers after Neoadjuvant Chemotherapy

Komal Jhaveri, Eleonora Teplinsky, Deborah Silvera, Amanda Valeta-Magara, Rezina Arju, Shah Giashuddin, Yasmeen Sarfraz, Melissa Alexander, Farbod Darvishian, Paul H. Levine, Salman Hashmi, Ladan Zolfaghari, Heather J. Hoffman, Baljit Singh, Judith D. Goldberg, Tsivia Hochman, Silvia Formenti, Francisco J. Esteva, Meena S. Moran, Robert J. Schneider

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

Introduction 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). Patients and 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. Conclusion 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.

Original languageEnglish
Pages (from-to)113-122.e1
JournalClinical Breast Cancer
Volume16
Issue number2
DOIs
StatePublished - 1 Apr 2016
Externally publishedYes

Keywords

  • Biomarkers
  • Inflammatory breast cancer
  • Resistance to chemotherapy
  • Signaling pathways
  • Targeted therapies

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