Estrogen-dependent DLL1-mediated Notch signaling promotes luminal breast cancer

Sushil Kumar, Ratnesh Kumar Srivastav, David W. Wilkes, Taylor Ross, Sabrina Kim, Jules Kowalski, Srinivas Chatla, Qing Zhang, Anupma Nayak, Manti Guha, Serge Y. Fuchs, Christoforos Thomas, Rumela Chakrabarti

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Aberrant Notch signaling is implicated in several cancers, including breast cancer. However, the mechanistic details of the specific receptors and function of ligand-mediated Notch signaling that promote breast cancer remains elusive. In our studies we show that DLL1, a Notch signaling ligand, is significantly overexpressed in ERα + luminal breast cancer. Intriguingly, DLL1 overexpression correlates with poor prognosis in ERα + luminal breast cancer, but not in other subtypes of breast cancer. In addition, this effect is specific to DLL1, as other Notch ligands (DLL3, JAGGED1, and JAGGED2) do not influence the clinical outcome of ERα + patients. Genetic studies show that DLL1-mediated Notch signaling in breast cancer is important for tumor cell proliferation, angiogenesis, and cancer stem cell function. Consistent with prognostic clinical data, we found the tumor-promoting function of DLL1 is exclusive to ERα + luminal breast cancer, as loss of DLL1 inhibits both tumor growth and lung metastasis of luminal breast cancer. Importantly, we find that estrogen signaling stabilizes DLL1 protein by preventing its proteasomal and lysososmal degradations. Moreover, estrogen inhibits ubiquitination of DLL1. Together, our results highlight an unexpected and novel subtype-specific function of DLL1 in promoting luminal breast cancer that is regulated by estrogen signaling. Our studies also emphasize the critical role of assessing subtype-specific mechanisms driving tumor growth and metastasis to generate effective subtype-specific therapeutics.

Original languageEnglish (US)
Pages (from-to)2092-2107
Number of pages16
JournalOncogene
Volume38
Issue number12
DOIs
StatePublished - Mar 21 2019
Externally publishedYes

Fingerprint

Estrogens
Breast Neoplasms
Ligands
Neoplasms
Neoplasm Metastasis
Neoplastic Stem Cells
Ubiquitination
Growth
Cell Proliferation
Lung

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Kumar, S., Srivastav, R. K., Wilkes, D. W., Ross, T., Kim, S., Kowalski, J., ... Chakrabarti, R. (2019). Estrogen-dependent DLL1-mediated Notch signaling promotes luminal breast cancer. Oncogene, 38(12), 2092-2107. https://doi.org/10.1038/s41388-018-0562-z

Estrogen-dependent DLL1-mediated Notch signaling promotes luminal breast cancer. / Kumar, Sushil; Srivastav, Ratnesh Kumar; Wilkes, David W.; Ross, Taylor; Kim, Sabrina; Kowalski, Jules; Chatla, Srinivas; Zhang, Qing; Nayak, Anupma; Guha, Manti; Fuchs, Serge Y.; Thomas, Christoforos; Chakrabarti, Rumela.

In: Oncogene, Vol. 38, No. 12, 21.03.2019, p. 2092-2107.

Research output: Contribution to journalArticle

Kumar, S, Srivastav, RK, Wilkes, DW, Ross, T, Kim, S, Kowalski, J, Chatla, S, Zhang, Q, Nayak, A, Guha, M, Fuchs, SY, Thomas, C & Chakrabarti, R 2019, 'Estrogen-dependent DLL1-mediated Notch signaling promotes luminal breast cancer', Oncogene, vol. 38, no. 12, pp. 2092-2107. https://doi.org/10.1038/s41388-018-0562-z
Kumar S, Srivastav RK, Wilkes DW, Ross T, Kim S, Kowalski J et al. Estrogen-dependent DLL1-mediated Notch signaling promotes luminal breast cancer. Oncogene. 2019 Mar 21;38(12):2092-2107. https://doi.org/10.1038/s41388-018-0562-z
Kumar, Sushil ; Srivastav, Ratnesh Kumar ; Wilkes, David W. ; Ross, Taylor ; Kim, Sabrina ; Kowalski, Jules ; Chatla, Srinivas ; Zhang, Qing ; Nayak, Anupma ; Guha, Manti ; Fuchs, Serge Y. ; Thomas, Christoforos ; Chakrabarti, Rumela. / Estrogen-dependent DLL1-mediated Notch signaling promotes luminal breast cancer. In: Oncogene. 2019 ; Vol. 38, No. 12. pp. 2092-2107.
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abstract = "Aberrant Notch signaling is implicated in several cancers, including breast cancer. However, the mechanistic details of the specific receptors and function of ligand-mediated Notch signaling that promote breast cancer remains elusive. In our studies we show that DLL1, a Notch signaling ligand, is significantly overexpressed in ERα + luminal breast cancer. Intriguingly, DLL1 overexpression correlates with poor prognosis in ERα + luminal breast cancer, but not in other subtypes of breast cancer. In addition, this effect is specific to DLL1, as other Notch ligands (DLL3, JAGGED1, and JAGGED2) do not influence the clinical outcome of ERα + patients. Genetic studies show that DLL1-mediated Notch signaling in breast cancer is important for tumor cell proliferation, angiogenesis, and cancer stem cell function. Consistent with prognostic clinical data, we found the tumor-promoting function of DLL1 is exclusive to ERα + luminal breast cancer, as loss of DLL1 inhibits both tumor growth and lung metastasis of luminal breast cancer. Importantly, we find that estrogen signaling stabilizes DLL1 protein by preventing its proteasomal and lysososmal degradations. Moreover, estrogen inhibits ubiquitination of DLL1. Together, our results highlight an unexpected and novel subtype-specific function of DLL1 in promoting luminal breast cancer that is regulated by estrogen signaling. Our studies also emphasize the critical role of assessing subtype-specific mechanisms driving tumor growth and metastasis to generate effective subtype-specific therapeutics.",
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