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

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.

Serum levels of inflammation‐related markers and metabolites predict response to neoadjuvant chemotherapy with and without bevacizumab in breast cancers

“…i ), delta‐like protein 1 (DLL1; Supplementary Fig. S1 f ), involved in promoting luminal breast cancer and CRP (Supplementary Fig. S1 i ) which has previously been monitored during neoadjuvant breast cancer therapy .…”

“…In the chemotherapy-only arm, lower levels of four cytokines were associated with response (i.e., AXL, DLL1, sTNFR1 and CRP). Of these, four AXL has been associated with epithelial mesenchymal transition and resistance to therapy, 30,36 DLL1, a Notch ligand, promotes ER-positive 21 and ER-negative 37 breast cancer carcinogenesis, while sTNFR1 has been associated with the risk of breast cancer. 38 These results suggest that these known oncogenic molecules at the tumor site could be monitored systemically and still relate to response.…”

Discrete and continuum phenotype-structured models for the evolution of cancer cell populations under chemotherapy

“…We study evolutionary dynamics of a well-mixed population of cancer cells structured by the expression level y ∈ R ≥0 of an epigenetically regulated gene that controls both cell proliferation and chemoresistance, such as the DLL1 gene [47,67,72]. Cells within the population divide, die and undergo spontaneous epimutations, i.e.…”

MicroRNA-3163 targets ADAM-17 and enhances the sensitivity of hepatocellular carcinoma cells to molecular targeted agents

“…The Notch signaling pathway is a key regulator of cellular fate, survival, and cellular stress/cellular injury responses in HCC cells 17,18 . The aberrant expression of Notch protein or activation of the Notch pathway has been reported in various malignancies, such as prostate cancer, colorectal cancer, breast cancer, and especially in HCC [19][20][21][22][23] . During clinical treatment, radiotherapy (ionizing radiation) or chemotherapeutic agents (cellular toxicity) may function as cellular injuries to HCC cells, activating Notch.…”