Constitutive activation of NF-κB during progression of breast cancer to hormone-independent growth

Harikrishna Nakshatri, Poornima Bhat-Nakshatri, Daniel A. Martin, Robert J. Goulet, George W. Sledge

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Abstract

Breast cancers often progress from a hormone-dependent, nonmetastatic, antiestrogen-sensitive phenotype to a hormone-independent, antiestrogen- and chemotherapy-resistant phenotype with highly invasive and metastatic growth properties. This progression is usually accompanied by altered function of the estrogen receptor (ER) or outgrowth of ER-negative cancer cells. To understand the molecular mechanisms responsible for metastatic growth of ER- negative breast cancers, the activities of the transcription factor NF-κB (which modulates the expression of genes involved in cell proliferation, differentiation, apoptosis, and metastasis) were compared in ER-positive (MCF-7 and T47-D) and ER-negative (MDA-MB-231 and MDA-MB-435) human breast cancer cell lines. NF-κB, which is usually maintained in an inactive state by protein-protein interaction with inhibitor IκBs, was found to be constitutively active in ER-negative breast cancer cell lines. Constitutive DNA binding of NF-κB was also observed with extracts from ER-negative, poorly differentiated primary breast tumors. Progression of the rat mammary carcinoma cell line RM22-F5 from an ER-positive, nonmalignant phenotype (E phenotype) to an ER-negative, malignant phenotype (F phenotype) was also accompanied by constitutive activation of NF-κB. Analysis of individual subunits of NF-κB revealed that all ER-negative cell lines, including RM22- F5 cells of F phenotype, contain a unique 37-kDa protein which is antigenically related to the RelA subunit. Cell-type-specific differences in IκBα, -β, and -γ were also observed. In transient-transfection experiments, constitutive activity of an NF-κB-dependent promoter was observed in MDA-MB-231 and RM22-F5 cells of F phenotype, and this activity was efficiently repressed by cotransfected ER. Since ER inhibits the constitutive as well as inducible activation function of NF-κB in a dose- dependent manner, we propose that breast cancers that lack functional ER overexpress NF-κB-regulated genes. Furthermore, since recent data indicate that NF-κB protects cells from tumor necrosis factor alpha-, ionizing radiation-, and chemotherapeutic agent daunorubicin-mediated apoptosis, our results provide an explanation for chemotherapeutic resistance in ER-negative breast cancers.

Original languageEnglish
Pages (from-to)3629-3639
Number of pages11
JournalMolecular and Cellular Biology
Volume17
Issue number7
StatePublished - Jul 1997

Fingerprint

Estrogen Receptors
Growth Hormone
Breast Neoplasms
Phenotype
Cell Line
Estrogen Receptor Modulators
Hormones
Alpha Particles
Apoptosis
Proteins
Daunorubicin
Growth
Ionizing Radiation
Transfection
Cell Differentiation
Transcription Factors
Tumor Necrosis Factor-alpha
Cell Proliferation
Neoplasm Metastasis

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Nakshatri, H., Bhat-Nakshatri, P., Martin, D. A., Goulet, R. J., & Sledge, G. W. (1997). Constitutive activation of NF-κB during progression of breast cancer to hormone-independent growth. Molecular and Cellular Biology, 17(7), 3629-3639.

Constitutive activation of NF-κB during progression of breast cancer to hormone-independent growth. / Nakshatri, Harikrishna; Bhat-Nakshatri, Poornima; Martin, Daniel A.; Goulet, Robert J.; Sledge, George W.

In: Molecular and Cellular Biology, Vol. 17, No. 7, 07.1997, p. 3629-3639.

Research output: Contribution to journalArticle

Nakshatri, H, Bhat-Nakshatri, P, Martin, DA, Goulet, RJ & Sledge, GW 1997, 'Constitutive activation of NF-κB during progression of breast cancer to hormone-independent growth', Molecular and Cellular Biology, vol. 17, no. 7, pp. 3629-3639.
Nakshatri, Harikrishna ; Bhat-Nakshatri, Poornima ; Martin, Daniel A. ; Goulet, Robert J. ; Sledge, George W. / Constitutive activation of NF-κB during progression of breast cancer to hormone-independent growth. In: Molecular and Cellular Biology. 1997 ; Vol. 17, No. 7. pp. 3629-3639.
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abstract = "Breast cancers often progress from a hormone-dependent, nonmetastatic, antiestrogen-sensitive phenotype to a hormone-independent, antiestrogen- and chemotherapy-resistant phenotype with highly invasive and metastatic growth properties. This progression is usually accompanied by altered function of the estrogen receptor (ER) or outgrowth of ER-negative cancer cells. To understand the molecular mechanisms responsible for metastatic growth of ER- negative breast cancers, the activities of the transcription factor NF-κB (which modulates the expression of genes involved in cell proliferation, differentiation, apoptosis, and metastasis) were compared in ER-positive (MCF-7 and T47-D) and ER-negative (MDA-MB-231 and MDA-MB-435) human breast cancer cell lines. NF-κB, which is usually maintained in an inactive state by protein-protein interaction with inhibitor IκBs, was found to be constitutively active in ER-negative breast cancer cell lines. Constitutive DNA binding of NF-κB was also observed with extracts from ER-negative, poorly differentiated primary breast tumors. Progression of the rat mammary carcinoma cell line RM22-F5 from an ER-positive, nonmalignant phenotype (E phenotype) to an ER-negative, malignant phenotype (F phenotype) was also accompanied by constitutive activation of NF-κB. Analysis of individual subunits of NF-κB revealed that all ER-negative cell lines, including RM22- F5 cells of F phenotype, contain a unique 37-kDa protein which is antigenically related to the RelA subunit. Cell-type-specific differences in IκBα, -β, and -γ were also observed. In transient-transfection experiments, constitutive activity of an NF-κB-dependent promoter was observed in MDA-MB-231 and RM22-F5 cells of F phenotype, and this activity was efficiently repressed by cotransfected ER. Since ER inhibits the constitutive as well as inducible activation function of NF-κB in a dose- dependent manner, we propose that breast cancers that lack functional ER overexpress NF-κB-regulated genes. Furthermore, since recent data indicate that NF-κB protects cells from tumor necrosis factor alpha-, ionizing radiation-, and chemotherapeutic agent daunorubicin-mediated apoptosis, our results provide an explanation for chemotherapeutic resistance in ER-negative breast cancers.",
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