NOTCH3 expression is linked to breast cancer seeding and distant metastasis

Aldo Di Leonardo, Judy Boughey, Tufia Haddad, Candace Haddox, Lisa Mills, Mario W. Gambino, Alexey A. Leontovich, James N. Ingle, Mohammad Jalalirad, Ann Tuma, Luca Zammataro, Antonino B. D'Assoro, Jann Sarkaria, Evanthia Galanis, Maria E. Guicciardi, James Mccubrey, Matthew Goetz, Jeffrey L. Salisbury, Mark Schroeder, Carol A. LangeLiewei Wang, Minetta Liu, Angela Amato

Risultato della ricerca: Article

9 Citazioni (Scopus)

Abstract

Background: Development of distant metastases involves a complex multistep biological process termed the invasion-metastasis cascade, which includes dissemination of cancer cells from the primary tumor to secondary organs. NOTCH developmental signaling plays a critical role in promoting epithelial-to-mesenchymal transition, tumor stemness, and metastasis. Although all four NOTCH receptors show oncogenic properties, the unique role of each of these receptors in the sequential stepwise events that typify the invasion-metastasis cascade remains elusive. Methods: We have established metastatic xenografts expressing high endogenous levels of NOTCH3 using estrogen receptor alpha-positive (ERα+) MCF-7 breast cancer cells with constitutive active Raf-1/mitogen-associated protein kinase (MAPK) signaling (vMCF-7Raf-1) and MDA-MB-231 triple-negative breast cancer (TNBC) cells. The critical role of NOTCH3 in inducing an invasive phenotype and poor outcome was corroborated in unique TNBC cells resulting from a patient-derived brain metastasis (TNBC-M25) and in publicly available claudin-low breast tumor specimens collected from participants in the Molecular Taxonomy of Breast Cancer International Consortium database. Results: In this study, we identified an association between NOTCH3 expression and development of metastases in ERα+and TNBC models. ERα+breast tumor xenografts with a constitutive active Raf-1/MAPK signaling developed spontaneous lung metastases through the clonal expansion of cancer cells expressing a NOTCH3 reprogramming network. Abrogation of NOTCH3 expression significantly reduced the self-renewal and invasive capacity of ex vivo breast cancer cells, restoring a luminal CD44low/CD24high/ERαhighphenotype. Forced expression of the mitotic Aurora kinase A (AURKA), which promotes breast cancer metastases, failed to restore the invasive capacity of NOTCH3-null cells, demonstrating that NOTCH3 expression is required for an invasive phenotype. Likewise, pharmacologic inhibition of NOTCH signaling also impaired TNBC cell seeding and metastatic growth. Significantly, the role of aberrant NOTCH3 expression in promoting tumor self-renewal, invasiveness, and poor outcome was corroborated in unique TNBC cells from a patient-derived brain metastasis and in publicly available claudin-low breast tumor specimens. Conclusions: These findings demonstrate the key role of NOTCH3 oncogenic signaling in the genesis of breast cancer metastasis and provide a compelling preclinical rationale for the design of novel therapeutic strategies that will selectively target NOTCH3 to halt metastatic seeding and to improve the clinical outcomes of patients with breast cancer.
Lingua originaleEnglish
pagine (da-a)105-
Numero di pagine19
RivistaBreast Cancer Research
Volume20
Stato di pubblicazionePublished - 2018

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Triple Negative Breast Neoplasms
Breast Neoplasms
Neoplasm Metastasis
Neoplasms
Mitogens
Heterografts
Protein Kinases
Aurora Kinase A
Phenotype
Biological Phenomena
Null Lymphocytes
Epithelial-Mesenchymal Transition
Estrogen Receptor alpha
Brain
Databases
Lung
Growth

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cita questo

Di Leonardo, A., Boughey, J., Haddad, T., Haddox, C., Mills, L., Gambino, M. W., ... Amato, A. (2018). NOTCH3 expression is linked to breast cancer seeding and distant metastasis. Breast Cancer Research, 20, 105-.

NOTCH3 expression is linked to breast cancer seeding and distant metastasis. / Di Leonardo, Aldo; Boughey, Judy; Haddad, Tufia; Haddox, Candace; Mills, Lisa; Gambino, Mario W.; Leontovich, Alexey A.; Ingle, James N.; Jalalirad, Mohammad; Tuma, Ann; Zammataro, Luca; D'Assoro, Antonino B.; Sarkaria, Jann; Galanis, Evanthia; Guicciardi, Maria E.; Mccubrey, James; Goetz, Matthew; Salisbury, Jeffrey L.; Schroeder, Mark; Lange, Carol A.; Wang, Liewei; Liu, Minetta; Amato, Angela.

In: Breast Cancer Research, Vol. 20, 2018, pag. 105-.

Risultato della ricerca: Article

Di Leonardo, A, Boughey, J, Haddad, T, Haddox, C, Mills, L, Gambino, MW, Leontovich, AA, Ingle, JN, Jalalirad, M, Tuma, A, Zammataro, L, D'Assoro, AB, Sarkaria, J, Galanis, E, Guicciardi, ME, Mccubrey, J, Goetz, M, Salisbury, JL, Schroeder, M, Lange, CA, Wang, L, Liu, M & Amato, A 2018, 'NOTCH3 expression is linked to breast cancer seeding and distant metastasis', Breast Cancer Research, vol. 20, pagg. 105-.
Di Leonardo A, Boughey J, Haddad T, Haddox C, Mills L, Gambino MW e altri. NOTCH3 expression is linked to breast cancer seeding and distant metastasis. Breast Cancer Research. 2018;20:105-.
Di Leonardo, Aldo ; Boughey, Judy ; Haddad, Tufia ; Haddox, Candace ; Mills, Lisa ; Gambino, Mario W. ; Leontovich, Alexey A. ; Ingle, James N. ; Jalalirad, Mohammad ; Tuma, Ann ; Zammataro, Luca ; D'Assoro, Antonino B. ; Sarkaria, Jann ; Galanis, Evanthia ; Guicciardi, Maria E. ; Mccubrey, James ; Goetz, Matthew ; Salisbury, Jeffrey L. ; Schroeder, Mark ; Lange, Carol A. ; Wang, Liewei ; Liu, Minetta ; Amato, Angela. / NOTCH3 expression is linked to breast cancer seeding and distant metastasis. In: Breast Cancer Research. 2018 ; Vol. 20. pagg. 105-.
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title = "NOTCH3 expression is linked to breast cancer seeding and distant metastasis",
abstract = "Background: Development of distant metastases involves a complex multistep biological process termed the invasion-metastasis cascade, which includes dissemination of cancer cells from the primary tumor to secondary organs. NOTCH developmental signaling plays a critical role in promoting epithelial-to-mesenchymal transition, tumor stemness, and metastasis. Although all four NOTCH receptors show oncogenic properties, the unique role of each of these receptors in the sequential stepwise events that typify the invasion-metastasis cascade remains elusive. Methods: We have established metastatic xenografts expressing high endogenous levels of NOTCH3 using estrogen receptor alpha-positive (ERα+) MCF-7 breast cancer cells with constitutive active Raf-1/mitogen-associated protein kinase (MAPK) signaling (vMCF-7Raf-1) and MDA-MB-231 triple-negative breast cancer (TNBC) cells. The critical role of NOTCH3 in inducing an invasive phenotype and poor outcome was corroborated in unique TNBC cells resulting from a patient-derived brain metastasis (TNBC-M25) and in publicly available claudin-low breast tumor specimens collected from participants in the Molecular Taxonomy of Breast Cancer International Consortium database. Results: In this study, we identified an association between NOTCH3 expression and development of metastases in ERα+and TNBC models. ERα+breast tumor xenografts with a constitutive active Raf-1/MAPK signaling developed spontaneous lung metastases through the clonal expansion of cancer cells expressing a NOTCH3 reprogramming network. Abrogation of NOTCH3 expression significantly reduced the self-renewal and invasive capacity of ex vivo breast cancer cells, restoring a luminal CD44low/CD24high/ERαhighphenotype. Forced expression of the mitotic Aurora kinase A (AURKA), which promotes breast cancer metastases, failed to restore the invasive capacity of NOTCH3-null cells, demonstrating that NOTCH3 expression is required for an invasive phenotype. Likewise, pharmacologic inhibition of NOTCH signaling also impaired TNBC cell seeding and metastatic growth. Significantly, the role of aberrant NOTCH3 expression in promoting tumor self-renewal, invasiveness, and poor outcome was corroborated in unique TNBC cells from a patient-derived brain metastasis and in publicly available claudin-low breast tumor specimens. Conclusions: These findings demonstrate the key role of NOTCH3 oncogenic signaling in the genesis of breast cancer metastasis and provide a compelling preclinical rationale for the design of novel therapeutic strategies that will selectively target NOTCH3 to halt metastatic seeding and to improve the clinical outcomes of patients with breast cancer.",
author = "{Di Leonardo}, Aldo and Judy Boughey and Tufia Haddad and Candace Haddox and Lisa Mills and Gambino, {Mario W.} and Leontovich, {Alexey A.} and Ingle, {James N.} and Mohammad Jalalirad and Ann Tuma and Luca Zammataro and D'Assoro, {Antonino B.} and Jann Sarkaria and Evanthia Galanis and Guicciardi, {Maria E.} and James Mccubrey and Matthew Goetz and Salisbury, {Jeffrey L.} and Mark Schroeder and Lange, {Carol A.} and Liewei Wang and Minetta Liu and Angela Amato",
year = "2018",
language = "English",
volume = "20",
pages = "105--",
journal = "Breast Cancer Research",
issn = "1465-5411",
publisher = "BioMed Central",

}

TY - JOUR

T1 - NOTCH3 expression is linked to breast cancer seeding and distant metastasis

AU - Di Leonardo, Aldo

AU - Boughey, Judy

AU - Haddad, Tufia

AU - Haddox, Candace

AU - Mills, Lisa

AU - Gambino, Mario W.

AU - Leontovich, Alexey A.

AU - Ingle, James N.

AU - Jalalirad, Mohammad

AU - Tuma, Ann

AU - Zammataro, Luca

AU - D'Assoro, Antonino B.

AU - Sarkaria, Jann

AU - Galanis, Evanthia

AU - Guicciardi, Maria E.

AU - Mccubrey, James

AU - Goetz, Matthew

AU - Salisbury, Jeffrey L.

AU - Schroeder, Mark

AU - Lange, Carol A.

AU - Wang, Liewei

AU - Liu, Minetta

AU - Amato, Angela

PY - 2018

Y1 - 2018

N2 - Background: Development of distant metastases involves a complex multistep biological process termed the invasion-metastasis cascade, which includes dissemination of cancer cells from the primary tumor to secondary organs. NOTCH developmental signaling plays a critical role in promoting epithelial-to-mesenchymal transition, tumor stemness, and metastasis. Although all four NOTCH receptors show oncogenic properties, the unique role of each of these receptors in the sequential stepwise events that typify the invasion-metastasis cascade remains elusive. Methods: We have established metastatic xenografts expressing high endogenous levels of NOTCH3 using estrogen receptor alpha-positive (ERα+) MCF-7 breast cancer cells with constitutive active Raf-1/mitogen-associated protein kinase (MAPK) signaling (vMCF-7Raf-1) and MDA-MB-231 triple-negative breast cancer (TNBC) cells. The critical role of NOTCH3 in inducing an invasive phenotype and poor outcome was corroborated in unique TNBC cells resulting from a patient-derived brain metastasis (TNBC-M25) and in publicly available claudin-low breast tumor specimens collected from participants in the Molecular Taxonomy of Breast Cancer International Consortium database. Results: In this study, we identified an association between NOTCH3 expression and development of metastases in ERα+and TNBC models. ERα+breast tumor xenografts with a constitutive active Raf-1/MAPK signaling developed spontaneous lung metastases through the clonal expansion of cancer cells expressing a NOTCH3 reprogramming network. Abrogation of NOTCH3 expression significantly reduced the self-renewal and invasive capacity of ex vivo breast cancer cells, restoring a luminal CD44low/CD24high/ERαhighphenotype. Forced expression of the mitotic Aurora kinase A (AURKA), which promotes breast cancer metastases, failed to restore the invasive capacity of NOTCH3-null cells, demonstrating that NOTCH3 expression is required for an invasive phenotype. Likewise, pharmacologic inhibition of NOTCH signaling also impaired TNBC cell seeding and metastatic growth. Significantly, the role of aberrant NOTCH3 expression in promoting tumor self-renewal, invasiveness, and poor outcome was corroborated in unique TNBC cells from a patient-derived brain metastasis and in publicly available claudin-low breast tumor specimens. Conclusions: These findings demonstrate the key role of NOTCH3 oncogenic signaling in the genesis of breast cancer metastasis and provide a compelling preclinical rationale for the design of novel therapeutic strategies that will selectively target NOTCH3 to halt metastatic seeding and to improve the clinical outcomes of patients with breast cancer.

AB - Background: Development of distant metastases involves a complex multistep biological process termed the invasion-metastasis cascade, which includes dissemination of cancer cells from the primary tumor to secondary organs. NOTCH developmental signaling plays a critical role in promoting epithelial-to-mesenchymal transition, tumor stemness, and metastasis. Although all four NOTCH receptors show oncogenic properties, the unique role of each of these receptors in the sequential stepwise events that typify the invasion-metastasis cascade remains elusive. Methods: We have established metastatic xenografts expressing high endogenous levels of NOTCH3 using estrogen receptor alpha-positive (ERα+) MCF-7 breast cancer cells with constitutive active Raf-1/mitogen-associated protein kinase (MAPK) signaling (vMCF-7Raf-1) and MDA-MB-231 triple-negative breast cancer (TNBC) cells. The critical role of NOTCH3 in inducing an invasive phenotype and poor outcome was corroborated in unique TNBC cells resulting from a patient-derived brain metastasis (TNBC-M25) and in publicly available claudin-low breast tumor specimens collected from participants in the Molecular Taxonomy of Breast Cancer International Consortium database. Results: In this study, we identified an association between NOTCH3 expression and development of metastases in ERα+and TNBC models. ERα+breast tumor xenografts with a constitutive active Raf-1/MAPK signaling developed spontaneous lung metastases through the clonal expansion of cancer cells expressing a NOTCH3 reprogramming network. Abrogation of NOTCH3 expression significantly reduced the self-renewal and invasive capacity of ex vivo breast cancer cells, restoring a luminal CD44low/CD24high/ERαhighphenotype. Forced expression of the mitotic Aurora kinase A (AURKA), which promotes breast cancer metastases, failed to restore the invasive capacity of NOTCH3-null cells, demonstrating that NOTCH3 expression is required for an invasive phenotype. Likewise, pharmacologic inhibition of NOTCH signaling also impaired TNBC cell seeding and metastatic growth. Significantly, the role of aberrant NOTCH3 expression in promoting tumor self-renewal, invasiveness, and poor outcome was corroborated in unique TNBC cells from a patient-derived brain metastasis and in publicly available claudin-low breast tumor specimens. Conclusions: These findings demonstrate the key role of NOTCH3 oncogenic signaling in the genesis of breast cancer metastasis and provide a compelling preclinical rationale for the design of novel therapeutic strategies that will selectively target NOTCH3 to halt metastatic seeding and to improve the clinical outcomes of patients with breast cancer.

UR - http://hdl.handle.net/10447/301687

UR - http://breast-cancer-research.com/

M3 - Article

VL - 20

SP - 105-

JO - Breast Cancer Research

JF - Breast Cancer Research

SN - 1465-5411

ER -