TY - JOUR
T1 - Estrogen-dependent DLL1-mediated Notch signaling promotes luminal breast cancer
AU - Kumar, Sushil
AU - Srivastav, Ratnesh Kumar
AU - Wilkes, David W.
AU - Ross, Taylor
AU - Kim, Sabrina
AU - Kowalski, Jules
AU - Chatla, Srinivas
AU - Zhang, Qing
AU - Nayak, Anupma
AU - Guha, Manti
AU - Fuchs, Serge Y.
AU - Thomas, Christoforos
AU - Chakrabarti, Rumela
N1 - Publisher Copyright:
© 2018, The Author(s).
PY - 2019/3/21
Y1 - 2019/3/21
N2 - 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.
AB - 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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U2 - 10.1038/s41388-018-0562-z
DO - 10.1038/s41388-018-0562-z
M3 - Article
C2 - 30442981
AN - SCOPUS:85056633815
SN - 0950-9232
VL - 38
SP - 2092
EP - 2107
JO - Oncogene
JF - Oncogene
IS - 12
ER -