STAT3 in breast cancer onset and progression: A matter of time and context

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Abstract

Signal transducer and activator of transcription 3 (STAT3) is responsible for mediating the transcriptional programs downstream of several cytokine, growth factor, and oncogenic stimuli. Its expression and activity are consistently linked to cellular transformation, as well as tumor initiation and progression. Due to this central role, STAT3 is widely considered a good target for anti-cancer therapy; however, the success of these approaches has been, so far, very limited. Notably, on one side, STAT3 is aberrantly active in many breast cancers, on the other, at the physiological level, it is the main mediator of epithelial cell death during post-lactation mammary-gland involution, thus strongly suggesting that its biological functions are highly context-specific. One of the most peculiar features of STAT3 is that it can act both in cell-autonomous and non-cell-autonomous manners, simultaneously modulating the phenotypes of the tumor cells and their microenvironment. Here, we focus on the role of STAT3 in breast cancer progression, discussing the potential contrasting roles of STAT3 activation in the establishment of locally recurrent and distant metastatic disease. Based on the most recent literature, depending on the tumor cell type, the local microenvironment status, and the stage of the disease, either STAT3 activation or inactivation can support disease progression. Accordingly, cancer cells dynamically exploit STAT3 activity to carry out transcriptional programs somehow contrasting and complementary, such as supporting survival and growth, dormancy and awakening, stem cell-like features, and inflammation, immune response, and immune evasion. As a consequence, to achieve clinical efficacy, the conception and testing of anti-STAT3 targeted therapies will need a very careful evaluation of these opposing roles and of the most appropriate tumor context, disease stage and patient population to treat.

Original languageEnglish
Article number2818
JournalInternational Journal of Molecular Sciences
Volume19
Issue number9
DOIs
Publication statusPublished - Sep 18 2018

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STAT3 Transcription Factor
Transcription
progressions
breast
Transducers
transducers
cancer
Breast Neoplasms
Tumors
tumors
Cellular Microenvironment
Neoplasms
Cells
Transcriptional Activation
therapy
mammary glands
Chemical activation
activation
Immune Evasion
phenotype

Keywords

  • Breast cancer
  • Dormancy
  • Inflammation
  • Local recurrence
  • Mammary epithelial cells
  • Metastasis
  • Mutation
  • STAT3

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

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title = "STAT3 in breast cancer onset and progression: A matter of time and context",
abstract = "Signal transducer and activator of transcription 3 (STAT3) is responsible for mediating the transcriptional programs downstream of several cytokine, growth factor, and oncogenic stimuli. Its expression and activity are consistently linked to cellular transformation, as well as tumor initiation and progression. Due to this central role, STAT3 is widely considered a good target for anti-cancer therapy; however, the success of these approaches has been, so far, very limited. Notably, on one side, STAT3 is aberrantly active in many breast cancers, on the other, at the physiological level, it is the main mediator of epithelial cell death during post-lactation mammary-gland involution, thus strongly suggesting that its biological functions are highly context-specific. One of the most peculiar features of STAT3 is that it can act both in cell-autonomous and non-cell-autonomous manners, simultaneously modulating the phenotypes of the tumor cells and their microenvironment. Here, we focus on the role of STAT3 in breast cancer progression, discussing the potential contrasting roles of STAT3 activation in the establishment of locally recurrent and distant metastatic disease. Based on the most recent literature, depending on the tumor cell type, the local microenvironment status, and the stage of the disease, either STAT3 activation or inactivation can support disease progression. Accordingly, cancer cells dynamically exploit STAT3 activity to carry out transcriptional programs somehow contrasting and complementary, such as supporting survival and growth, dormancy and awakening, stem cell-like features, and inflammation, immune response, and immune evasion. As a consequence, to achieve clinical efficacy, the conception and testing of anti-STAT3 targeted therapies will need a very careful evaluation of these opposing roles and of the most appropriate tumor context, disease stage and patient population to treat.",
keywords = "Breast cancer, Dormancy, Inflammation, Local recurrence, Mammary epithelial cells, Metastasis, Mutation, STAT3",
author = "Ilenia Segatto and Gustavo Baldassarre and Barbara Belletti",
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doi = "10.3390/ijms19092818",
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T1 - STAT3 in breast cancer onset and progression

T2 - A matter of time and context

AU - Segatto, Ilenia

AU - Baldassarre, Gustavo

AU - Belletti, Barbara

PY - 2018/9/18

Y1 - 2018/9/18

N2 - Signal transducer and activator of transcription 3 (STAT3) is responsible for mediating the transcriptional programs downstream of several cytokine, growth factor, and oncogenic stimuli. Its expression and activity are consistently linked to cellular transformation, as well as tumor initiation and progression. Due to this central role, STAT3 is widely considered a good target for anti-cancer therapy; however, the success of these approaches has been, so far, very limited. Notably, on one side, STAT3 is aberrantly active in many breast cancers, on the other, at the physiological level, it is the main mediator of epithelial cell death during post-lactation mammary-gland involution, thus strongly suggesting that its biological functions are highly context-specific. One of the most peculiar features of STAT3 is that it can act both in cell-autonomous and non-cell-autonomous manners, simultaneously modulating the phenotypes of the tumor cells and their microenvironment. Here, we focus on the role of STAT3 in breast cancer progression, discussing the potential contrasting roles of STAT3 activation in the establishment of locally recurrent and distant metastatic disease. Based on the most recent literature, depending on the tumor cell type, the local microenvironment status, and the stage of the disease, either STAT3 activation or inactivation can support disease progression. Accordingly, cancer cells dynamically exploit STAT3 activity to carry out transcriptional programs somehow contrasting and complementary, such as supporting survival and growth, dormancy and awakening, stem cell-like features, and inflammation, immune response, and immune evasion. As a consequence, to achieve clinical efficacy, the conception and testing of anti-STAT3 targeted therapies will need a very careful evaluation of these opposing roles and of the most appropriate tumor context, disease stage and patient population to treat.

AB - Signal transducer and activator of transcription 3 (STAT3) is responsible for mediating the transcriptional programs downstream of several cytokine, growth factor, and oncogenic stimuli. Its expression and activity are consistently linked to cellular transformation, as well as tumor initiation and progression. Due to this central role, STAT3 is widely considered a good target for anti-cancer therapy; however, the success of these approaches has been, so far, very limited. Notably, on one side, STAT3 is aberrantly active in many breast cancers, on the other, at the physiological level, it is the main mediator of epithelial cell death during post-lactation mammary-gland involution, thus strongly suggesting that its biological functions are highly context-specific. One of the most peculiar features of STAT3 is that it can act both in cell-autonomous and non-cell-autonomous manners, simultaneously modulating the phenotypes of the tumor cells and their microenvironment. Here, we focus on the role of STAT3 in breast cancer progression, discussing the potential contrasting roles of STAT3 activation in the establishment of locally recurrent and distant metastatic disease. Based on the most recent literature, depending on the tumor cell type, the local microenvironment status, and the stage of the disease, either STAT3 activation or inactivation can support disease progression. Accordingly, cancer cells dynamically exploit STAT3 activity to carry out transcriptional programs somehow contrasting and complementary, such as supporting survival and growth, dormancy and awakening, stem cell-like features, and inflammation, immune response, and immune evasion. As a consequence, to achieve clinical efficacy, the conception and testing of anti-STAT3 targeted therapies will need a very careful evaluation of these opposing roles and of the most appropriate tumor context, disease stage and patient population to treat.

KW - Breast cancer

KW - Dormancy

KW - Inflammation

KW - Local recurrence

KW - Mammary epithelial cells

KW - Metastasis

KW - Mutation

KW - STAT3

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