Notch promotes recurrence of dormant tumor cells following HER2/neu-targeted therapy

Abravanel, Daniel L.; Belka, George K.; Pan, Tien-Chi; Pant, Dhruv K.; Collins, Meredith A.; Sterner, Christopher J.; Chodosh, Lewis A.

doi:10.1172/jci74883

Cited by 115 publications

(112 citation statements)

References 91 publications

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“…4c and Extended Data Fig. 6c), confirming previous reports from HER2-amplified breast cancer cells 6,7 (Extended Data Fig. 6c).…”

supporting

confidence: 90%

“…The comparable tumor initiating potential and similar expression of stem cell marker ALDH1 in HER2+ and HER2− CTCs suggests underlying tumor cell plasticity in these advanced patient-derived breast CTC lines, rather than a hierarchical cancer stem cell model as described in drug resistant subpopulations within established breast cancer cell lines 7,10–15 . While expression of NOTCH1 and other embryonic markers has been reported in rare, quiescent cells within primary breast tumors 7,16,17,18 , the NOTCH1+ CTCs reported here constitute a major cell population, exhibiting both persistent cell proliferation in vitro and tumorigenesis in vivo . Thus, we propose a dynamic model, in which the equilibrium between HER2+ and HER2− cells within a heterogeneous tumor population is driven by spontaneous interconversion between these phenotypes, with the more rapidly proliferating HER2+ cells prevalent under baseline conditions, and environmental or therapy-induced stress enhancing conversion to the more resistant HER2− phenotype.…”

mentioning

confidence: 94%

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HER2 expression identifies dynamic functional states within circulating breast cancer cells

Jordan

Bardia

Wittner

et al. 2016

Nature

370

352

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Circulating tumor cells (CTCs) in women with advanced estrogen receptor-positive/HER2-negative breast cancer acquire a HER2-positive subpopulation following multiple courses of therapy1,2. In contrast to HER2-amplified primary breast cancer, which is highly sensitive to HER2-targeted therapy, the clinical significance of acquired HER2 heterogeneity during the evolution of metastatic breast cancer is unknown. Here, we analyzed CTCs from 19 ER+/HER2− patients, 84% of whom had acquired CTCs expressing HER2. Cultured CTCs maintain discrete HER2+ and HER2− subpopulations: HER2+ CTCs are more proliferative but not addicted to HER2, consistent with activation of multiple signaling pathways. HER2− CTCs show activation of Notch and DNA damage pathways, exhibiting resistance to cytotoxic chemotherapy, but sensitivity to Notch inhibition. HER2+ and HER2− CTCs interconvert spontaneously, with cells of one phenotype producing daughters of the opposite within four cell doublings. While HER2+ and HER2− CTCs have comparable tumor initiating potential, differential proliferation favors the HER2+ state, while oxidative stress or cytotoxic chemotherapy enhances transition to the HER2− phenotype. Simultaneous treatment with paclitaxel and Notch inhibitors achieves sustained suppression of tumorigenesis in orthotopic CTC-derived tumor models. Together, these results point to distinct yet interconverting phenotypes within patient-derived CTCs, contributing to progression of breast cancer and acquisition of drug resistance.

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“…4c and Extended Data Fig. 6c), confirming previous reports from HER2-amplified breast cancer cells 6,7 (Extended Data Fig. 6c).…”

supporting

confidence: 90%

mentioning

confidence: 94%

HER2 expression identifies dynamic functional states within circulating breast cancer cells

Jordan

Bardia

Wittner

et al. 2016

Nature

370

352

View full text Add to dashboard Cite

show abstract

“…Pan-Notch inhibition using GSIs supports this conclusion (13,35), although use of GSIs fails to distinguish the particular Notch receptor driving growth. In human cancers, the clearest cases supporting Notch as a tumor driver derive from genomic studies revealing Notch1 mutations in the (i) NRR, which activate signaling in a ligand-independent manner, and (ii) PEST domain, which prolong signaling.…”

Section: Discussionmentioning

confidence: 92%

Constitutive NOTCH3 Signaling Promotes the Growth of Basal Breast Cancers

Choy¹,

Hagenbeek²,

Solon³

et al. 2017

Cancer Research

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Notch ligands signal through one of four receptors on neighboring cells to mediate cell-cell communication and control cell fate, proliferation, and survival. Although aberrant Notch activation has been implicated in numerous malignancies, including breast cancer, the importance of individual receptors in distinct breast cancer subtypes and the mechanisms of receptor activation remain unclear. Using a novel antibody to detect active NOTCH3, we report here that NOTCH3 signals constitutively in a panel of basal breast cancer cell lines and in more than one third of basal tumors. Selective inhibition of individual ligands revealed that this signal does not require canonical ligand induction. A NOTCH3 antagonist antibody inhibited growth of basal lines, whereas a NOTCH3 agonist antibody enhanced the transformed phenotype in vitro and in tumor xenografts. Transcriptomic analyses generated a Notch gene signature that included Notch pathway components, the oncogene c-Myc, and the mammary stem cell regulator Id4. This signature drove clustering of breast cancer cell lines and tumors into the common subtypes and correlated with the basal classification. Our results highlight an unexpected ligand-independent induction mechanism and suggest that constitutive NOTCH3 signaling can drive an oncogenic program in a subset of basal breast cancers.

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“…Using a tumor model driven by HER2 , Chodosh and colleagues showed that although withdrawal of this oncogene results in tumor regression, mice ultimately develop recurrent tumors that have become HER2 independent (54), suggesting the existence of residual dormant tumor cells. Although Notch signaling was implicated in maintenance of dormancy, its inhibition did not inhibit tumor re-growth (55), suggesting that another pathway regulates the growth of recurrent tumors.…”

Section: Discussionmentioning

confidence: 99%

ERK and p38 MAPK Activities Determine Sensitivity to PI3K/mTOR Inhibition via Regulation of MYC and YAP

et al. 2016

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Aberrant activation of the PI3K/mTOR-pathway is a common feature of many cancers and an attractive target for therapy, but resistance inevitably evolves is as the case for any cancer cell targeted therapy. In animal tumor models, chronic inhibition of PI3K/mTOR initially inhibits tumor growth, but over time, tumor cells escape inhibition. In this study, we identified a context-dependent mechanism of escape whereby tumor cells upregulated the proto-oncogene transcriptional regulators c-MYC and YAP1. This mechanism was dependent on both constitutive ERK activity as well as inhibition of the stress kinase p38. Inhibition of p38 relieved proliferation arrest and allowed upregulation of MYC and YAP through stabilization of CREB. These data provide new insights into cellular signaling mechanisms that influence resistance to PI3K/mTOR inhibitors. Furthermore, they suggest that therapies that inactivate YAP or MYC or augment p38 activity could enhance the efficacy of PI3K/mTOR inhibitors.

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Notch promotes recurrence of dormant tumor cells following HER2/neu-targeted therapy

Cited by 115 publications

References 91 publications

HER2 expression identifies dynamic functional states within circulating breast cancer cells

HER2 expression identifies dynamic functional states within circulating breast cancer cells

Constitutive NOTCH3 Signaling Promotes the Growth of Basal Breast Cancers

ERK and p38 MAPK Activities Determine Sensitivity to PI3K/mTOR Inhibition via Regulation of MYC and YAP

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