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NF-κB as the main node of resistance to receptor tyrosine kinase inhibitors in triple-negative breast cancer.

Abstract Graphical abstract Although accounting for merely a minute portion of diagnosed breast cancers, disproportionate number of deaths and associated low survival rate of patients have made triple-negative breast cancer to be considered as the most lethal breast cancer subtype. More importantly, intrinsic or developed resistance to chemotherapeutic regimens and disappointing outcomes of trials associated with many newly developed agents are other obstacles in establishment of a durable response in these patients. Interestingly, these happen despite the outstanding preclinical outcomes observed by these agents, most importantly among them, targeted receptor tyrosine kinase inhibitors. Pursuing these disappointing outcomes, especially in the case of targeted receptor tyrosine kinase inhibitors, many researches have focused on identification of the hidden factors involved. Highly inflammatory, rich in reactive oxygen species, and hypoxic microenvironment of triple-negative breast cancer tumors and the involving mediators were the first suggestions for observed resistance and poor clinical outcomes of targeted receptor tyrosine kinase inhibitors. Interestingly, for all aberrantly expressed mediators observed in microenvironment, downstream pathways converge in a common node, nothing but the nuclear factor-κB, the insidious factor proposed to be the cause of many events opposing achievement of a desired outcome. In first section of current review, we describe the signaling pathways underlying activation of receptor tyrosine kinases and their convergence at the nuclear factor-κB node, and in next section, we demonstrate how unique hypoxic, inflammatory, rich in free-radical microenvironment of triple-negative breast cancer exacerbate pathways in which otherwise could become mostly suppressed by receptor tyrosine kinase inhibitors.
PMID
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Authors

Mayor MeshTerms
Keywords

Triple-negative breast cancer

chemotherapy resistance

nuclear factor-κB

receptor tyrosine kinase inhibitors

Journal Title tumour biology : the journal of the international society for oncodevelopmental biology and medicine
Publication Year Start




PMID- 28653902
OWN - NLM
STAT- MEDLINE
DA  - 20170627
DCOM- 20170711
LR  - 20170713
IS  - 1423-0380 (Electronic)
IS  - 1010-4283 (Linking)
VI  - 39
IP  - 6
DP  - 2017 Jun
TI  - NF-kappaB as the main node of resistance to receptor tyrosine kinase inhibitors
      in triple-negative breast cancer.
PG  - 1010428317706919
LID - 10.1177/1010428317706919 [doi]
AB  - Graphical abstract Although accounting for merely a minute portion of diagnosed
      breast cancers, disproportionate number of deaths and associated low survival
      rate of patients have made triple-negative breast cancer to be considered as the 
      most lethal breast cancer subtype. More importantly, intrinsic or developed
      resistance to chemotherapeutic regimens and disappointing outcomes of trials
      associated with many newly developed agents are other obstacles in establishment 
      of a durable response in these patients. Interestingly, these happen despite the 
      outstanding preclinical outcomes observed by these agents, most importantly among
      them, targeted receptor tyrosine kinase inhibitors. Pursuing these disappointing 
      outcomes, especially in the case of targeted receptor tyrosine kinase inhibitors,
      many researches have focused on identification of the hidden factors involved.
      Highly inflammatory, rich in reactive oxygen species, and hypoxic
      microenvironment of triple-negative breast cancer tumors and the involving
      mediators were the first suggestions for observed resistance and poor clinical
      outcomes of targeted receptor tyrosine kinase inhibitors. Interestingly, for all 
      aberrantly expressed mediators observed in microenvironment, downstream pathways 
      converge in a common node, nothing but the nuclear factor-kappaB, the insidious
      factor proposed to be the cause of many events opposing achievement of a desired 
      outcome. In first section of current review, we describe the signaling pathways
      underlying activation of receptor tyrosine kinases and their convergence at the
      nuclear factor-kappaB node, and in next section, we demonstrate how unique
      hypoxic, inflammatory, rich in free-radical microenvironment of triple-negative
      breast cancer exacerbate pathways in which otherwise could become mostly
      suppressed by receptor tyrosine kinase inhibitors.
FAU - Darvishi, Behrad
AU  - Darvishi B
AD  - 1 Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer 
      Institute, ACECR, Tehran, Iran.
FAU - Farahmand, Leila
AU  - Farahmand L
AD  - 1 Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer 
      Institute, ACECR, Tehran, Iran.
FAU - Eslami-S, Zahra
AU  - Eslami-S Z
AD  - 1 Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer 
      Institute, ACECR, Tehran, Iran.
FAU - Majidzadeh-A, Keivan
AU  - Majidzadeh-A K
AD  - 2 Genetics Department, Breast Cancer Research Center, Motamed Cancer Institute,
      ACECR, 1517964311 Tehran, Iran.
LA  - eng
PT  - Journal Article
PT  - Review
PL  - United States
TA  - Tumour Biol
JT  - Tumour biology : the journal of the International Society for Oncodevelopmental
      Biology and Medicine
JID - 8409922
RN  - 0 (NF-kappa B)
RN  - 0 (Reactive Oxygen Species)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
SB  - IM
MH  - Female
MH  - Humans
MH  - Inflammation/*genetics/pathology
MH  - NF-kappa B/*genetics
MH  - Reactive Oxygen Species/metabolism
MH  - Receptor, ErbB-2/genetics
MH  - Signal Transduction
MH  - Triple Negative Breast Neoplasms/*drug therapy/*genetics/pathology
OTO - NOTNLM
OT  - Triple-negative breast cancer
OT  - chemotherapy resistance
OT  - nuclear factor-kappaB
OT  - receptor tyrosine kinase inhibitors
EDAT- 2017/06/28 06:00
MHDA- 2017/07/14 06:00
CRDT- 2017/06/28 06:00
AID - 10.1177/1010428317706919 [doi]
PST - ppublish
SO  - Tumour Biol. 2017 Jun;39(6):1010428317706919. doi: 10.1177/1010428317706919.