Cyclin D1-Dependent Induction of Luminal Inflammatory Breast Tumors by Activated Notch3

Hua, Lei; Sylvestre, Jean Rene; Jolicoeur, Paul

doi:10.1158/0008-5472.can-13-0409

Cited by 13 publications

(6 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ICN3 inhibited tumor growth in cancer cell lines 49 . By contrast, ICN3 induced aggressive inflammatory breast cancer cells when expressed in the mammary stem/progenitor cells in mice 59 . Thus, it is possible that ICN1 may have differential roles in different subsets of intratumoral cells and/or premalignant cells.…”

Section: Discussionmentioning

confidence: 92%

Cellular senescence checkpoint function determines differential Notch1-dependent oncogenic and tumor-suppressor activities

Kagawa

Natsuizaka

et al. 2014

Oncogene

View full text Add to dashboard Cite

Notch activity regulates tumor biology in a context-dependent and complex manner. Notch may act as an oncogene or a tumor suppressor gene even within the same tumor type. Recently, Notch signaling has been implicated in cellular senescence. Yet, it remains unclear as to how cellular senescence checkpoint functions may interact with Notch-mediated oncogenic and tumor suppressor activities. Herein, we used genetically engineered human esophageal keratinocytes and esophageal squamous cell carcinoma cells to delineate the functional consequences of Notch activation and inhibition along with pharmacological intervention and RNA interference (RNAi) experiments. When expressed in a tetracycline-inducible manner, the ectopically expressed activated form of Notch1 (ICN1) displayed oncogene-like characteristics inducing cellular senescence corroborated by the induction of G0/G1 cell-cycle arrest, Rb dephosphorylation, flat and enlarged cell morphology and senescence-associated β-galactosidase activity. Notch-induced senescence involves canonical CSL/RBPJ-dependent transcriptional activity and the p16INK4A-Rb pathway. Loss of p16INK4A or the presence of human papilloma virus (HPV) E6/E7 oncogene products not only prevented ICN1 from inducing senescence, but permitted ICN1 to facilitate anchorage-independent colony formation and xenograft tumor growth with increased cell proliferation and reduced squamous-cell differentiation. Moreover, Notch1 appears to mediate replicative senescence as well as TGF-β-induced cellular senescence in non-transformed cells and that HPV E6/E7 targets Notch1 for inactivation to prevent senescence, revealing a tumor suppressor attribute of endogenous Notch1. In aggregate, cellular senescence checkpoint functions may influence dichotomous Notch activities in the neoplastic context.

show abstract

Section: Discussionmentioning

confidence: 92%

Cellular senescence checkpoint function determines differential Notch1-dependent oncogenic and tumor-suppressor activities

Kagawa

Natsuizaka

et al. 2014

Oncogene

View full text Add to dashboard Cite

show abstract

“…The FC‐IBC02 cell line shows NOTCH3 amplification (Fernandez et al , ). Pregnant mice expressing higher levels of an activated intracellular form of NOTCH3 develop luminal mammary tumors resembling IBC that frequently metastasize (Ling et al , ). Thus, the NOTCH targeting might be an option for IBC treatment.…”

Section: Discussionmentioning

confidence: 99%

NOTCH and DNA repair pathways are more frequently targeted by genomic alterations in inflammatory than in non‐inflammatory breast cancers

et al. 2020

View full text Add to dashboard Cite

Inflammatory breast cancer (IBC) is the most pro‐metastatic form of breast cancer. Better understanding of its pathophysiology and identification of actionable genetic alterations (AGAs) are crucial to improve systemic treatment. We aimed to define the DNA profiles of IBC vs noninflammatory breast cancer (non‐IBC) clinical samples in terms of copy number alterations (CNAs), mutations, and AGAs. We applied targeted next‐generation sequencing (tNGS) and array‐comparative genomic hybridization (aCGH) to 57 IBC and 50 non‐IBC samples and pooled these data with four public datasets profiled using NGS and aCGH, leading to a total of 101 IBC and 2351 non‐IBC untreated primary tumors. The respective percentages of each molecular subtype [hormone receptor‐positive (HR+)/HER2−, HER2+, and triple‐negative] were 68%, 15%, and 17% in non‐IBC vs 25%, 35%, and 40% in IBC. The comparisons were adjusted for both the molecular subtypes and the American Joint Committee on Cancer (AJCC) stage. The 10 most frequently altered genes in IBCs were TP53 (63%), HER2/ERBB2 (30%), MYC (27%), PIK3CA (21%), BRCA2 (14%), CCND1 (13%), GATA3 (13%), NOTCH1 (12%), FGFR1 (11%), and ARID1A (10%). The tumor mutational burden was higher in IBC than in non‐IBC. We identified 96 genes with an alteration frequency (p < 5% and q < 20%) different between IBC and non‐IBC, independently from the molecular subtypes and AJCC stage; 95 were more frequently altered in IBC, including TP53, genes involved in the DNA repair (BRCA2) and NOTCH pathways, and one (PIK3CA) was more frequently altered in non‐IBC. Ninety‐seven percent of IBCs displayed at least one AGA. This percentage was higher than in non‐IBC (87%), notably for drugs targeting DNA repair, NOTCH signaling, and CDK4/6, whose pathways were more frequently altered (DNA repair) or activated (NOTCH and CDK4/6) in IBC than in non‐IBC. The genomic landscape of IBC is different from that of non‐IBC. Enriched AGAs in IBC may explain its aggressiveness and provide clinically relevant targets.

show abstract

“…Notch3 (N3IC) mice that contain an activated intracellular form of Notch exhibit a cyclin D1-dependent expansion of CD24 + CD29 lo luminal progenitors. Transplants show reduced alveoli in pregnant hosts, with a higher proportion of cells expressing ERα [156], suggesting Notch3 may regulate hormone sensing cell populations. Examination of Notch4 signaling defined yet another type of luminal population.…”

Section: Parity and Progenitor Cell Populationsmentioning

confidence: 99%

Form and Function: how Estrogen and Progesterone Regulate the Mammary Epithelial Hierarchy

Arendt

Kuperwasser

2015

J Mammary Gland Biol Neoplasia

103

View full text Add to dashboard Cite

The mammary gland undergoes dramatic post-natal growth beginning at puberty, followed by full development occurring during pregnancy and lactation. Following lactation, the alveoli undergo apoptosis, and the mammary gland reverses back to resemble the nonparous gland. This process of growth and regression occurs for multiple pregnancies, suggesting the presence of a hierarchy of stem and progenitor cells that are able to regenerate specialized populations of mammary epithelial cells. Expansion of epithelial cell populations in the mammary gland is regulated by ovarian steroids, in particular estrogen acting through its receptor estrogen receptor alpha (ERα) and progesterone signaling through progesterone receptor (PR). A diverse number of stem and progenitor cells have been identified based on expression of cell surface markers and functional assays. Here we review the current understanding of how estrogen and progesterone act together and separately to regulate stem and progenitor cells within the human and mouse mammary tissues. Better understanding of the hierarchal organization of epithelial cell populations in the mammary gland and how the hormonal milieu affects its regulation may provide important insights into the origins of different subtypes of breast cancer.

show abstract

Cyclin D1-Dependent Induction of Luminal Inflammatory Breast Tumors by Activated Notch3

Abstract: Accumulating evidence suggests that Notch3 (N3) is involved in breast cancer development, but its precise contributions are not well understood. Here, we report that pregnant mice expressing an activated intracellular form of N3 (

Cited by 13 publications

References 49 publications

Cellular senescence checkpoint function determines differential Notch1-dependent oncogenic and tumor-suppressor activities

Cellular senescence checkpoint function determines differential Notch1-dependent oncogenic and tumor-suppressor activities

NOTCH and DNA repair pathways are more frequently targeted by genomic alterations in inflammatory than in non‐inflammatory breast cancers

Form and Function: how Estrogen and Progesterone Regulate the Mammary Epithelial Hierarchy

Contact Info

Product

Resources

About