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Clin Breast Cancer. 2016 Apr;16(2):113-22.e1. doi: 10.1016/j.clbc.2015.11.006. Epub 2015 Dec 1.

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

Author information

1
Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY. Electronic address: jhaverik@mskcc.org.
2
Division of Hematology & Medical Oncology, Department of Medicine, New York University School of Medicine, New York, NY.
3
Department of Microbiology, New York University School of Medicine, New York, NY.
4
Department of Pathology, The Brooklyn Hospital Center, Brooklyn, NY.
5
Department of Epidemiology and Biostatistics, George Washington University, Washington, DC.
6
Division of Biostatistics, New York University School of Medicine, New York, NY.
7
Department of Radiation Oncology, Weill Cornell Medical College, New York, NY.
8
Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY.
9
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT.
10
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.

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.

KEYWORDS:

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

PMID:
26774497
PMCID:
PMC4794410
DOI:
10.1016/j.clbc.2015.11.006
[Indexed for MEDLINE]
Free PMC Article

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