NOTCH3 expression is linked to breast cancer seeding and distant metastasis

Alexey A. Leontovich, Mohammad Jalalirad, Jeffrey L Salisbury, Lisa Mills, Candace Haddox, Mark Schroeder, Ann Tuma, Maria E. Guicciardi, Luca Zammataro, Mario W. Gambino, Angela Amato, Aldo Di Leonardo, James McCubrey, Carol A. Lange, Minetta C Liu, Tufia C Haddad, Matthew Philip Goetz, Judy C Boughey, Jann N Sarkaria, Liewei M Wang & 3 others James N. Ingle, Evanthia Galanis, Antonio D'Assoro

Research output: Contribution to journalArticle

7 Citations (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/ERαhigh phenotype. 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.

Original languageEnglish (US)
Article number105
JournalBreast Cancer Research
Volume20
Issue number1
DOIs
StatePublished - Sep 4 2018

Fingerprint

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

Keywords

  • Breast cancer
  • Centrosome amplification
  • Chromosomal instability
  • Metastasis
  • Tumor stemness

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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

In: Breast Cancer Research, Vol. 20, No. 1, 105, 04.09.2018.

Research output: Contribution to journalArticle

Leontovich, AA, Jalalirad, M, Salisbury, JL, Mills, L, Haddox, C, Schroeder, M, Tuma, A, Guicciardi, ME, Zammataro, L, Gambino, MW, Amato, A, Di Leonardo, A, McCubrey, J, Lange, CA, Liu, MC, Haddad, TC, Goetz, MP, Boughey, JC, Sarkaria, JN, Wang, LM, Ingle, JN, Galanis, E & D'Assoro, A 2018, 'NOTCH3 expression is linked to breast cancer seeding and distant metastasis', Breast Cancer Research, vol. 20, no. 1, 105. https://doi.org/10.1186/s13058-018-1020-0
Leontovich, Alexey A. ; Jalalirad, Mohammad ; Salisbury, Jeffrey L ; Mills, Lisa ; Haddox, Candace ; Schroeder, Mark ; Tuma, Ann ; Guicciardi, Maria E. ; Zammataro, Luca ; Gambino, Mario W. ; Amato, Angela ; Di Leonardo, Aldo ; McCubrey, James ; Lange, Carol A. ; Liu, Minetta C ; Haddad, Tufia C ; Goetz, Matthew Philip ; Boughey, Judy C ; Sarkaria, Jann N ; Wang, Liewei M ; Ingle, James N. ; Galanis, Evanthia ; D'Assoro, Antonio. / NOTCH3 expression is linked to breast cancer seeding and distant metastasis. In: Breast Cancer Research. 2018 ; Vol. 20, No. 1.
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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/ERαhigh phenotype. 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.",
keywords = "Breast cancer, Centrosome amplification, Chromosomal instability, Metastasis, Tumor stemness",
author = "Leontovich, {Alexey A.} and Mohammad Jalalirad and Salisbury, {Jeffrey L} and Lisa Mills and Candace Haddox and Mark Schroeder and Ann Tuma and Guicciardi, {Maria E.} and Luca Zammataro and Gambino, {Mario W.} and Angela Amato and {Di Leonardo}, Aldo and James McCubrey and Lange, {Carol A.} and Liu, {Minetta C} and Haddad, {Tufia C} and Goetz, {Matthew Philip} and Boughey, {Judy C} and Sarkaria, {Jann N} and Wang, {Liewei M} and Ingle, {James N.} and Evanthia Galanis and Antonio D'Assoro",
year = "2018",
month = "9",
day = "4",
doi = "10.1186/s13058-018-1020-0",
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TY - JOUR

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

AU - Leontovich, Alexey A.

AU - Jalalirad, Mohammad

AU - Salisbury, Jeffrey L

AU - Mills, Lisa

AU - Haddox, Candace

AU - Schroeder, Mark

AU - Tuma, Ann

AU - Guicciardi, Maria E.

AU - Zammataro, Luca

AU - Gambino, Mario W.

AU - Amato, Angela

AU - Di Leonardo, Aldo

AU - McCubrey, James

AU - Lange, Carol A.

AU - Liu, Minetta C

AU - Haddad, Tufia C

AU - Goetz, Matthew Philip

AU - Boughey, Judy C

AU - Sarkaria, Jann N

AU - Wang, Liewei M

AU - Ingle, James N.

AU - Galanis, Evanthia

AU - D'Assoro, Antonio

PY - 2018/9/4

Y1 - 2018/9/4

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/ERαhigh phenotype. 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/ERαhigh phenotype. 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.

KW - Breast cancer

KW - Centrosome amplification

KW - Chromosomal instability

KW - Metastasis

KW - Tumor stemness

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DO - 10.1186/s13058-018-1020-0

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