Cyclin D1 and C/EBPβ LAP1 Operate in a Common Pathway To Promote Mammary Epithelial Cell Differentiation

Liu, Qiang; Boudot, Antoine; Ni, Jing; Hennessey, Timothy L.; Beauparlant, Stephen L.; Rajabi, Hasan; Zahnow, Cynthia A.; Ewen, Mark E.

doi:10.1128/mcb.00039-14

Cited by 15 publications

(8 citation statements)

References 39 publications

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“…Retroviral production was performed as described previously. 19 Lentiviral short hairpin (sh)RNA constructs in the pLKO.1 vector were obtained from the RNAi Core Facility at DanaFarber Cancer Institute. The shRNA sequences targeting mouse Stat3 are listed in the Supplementary Table. Lentivirus preparation and transduction of cells were performed according to the online protocol of the RNAi Core Facility.…”

Section: Plasmid Constructs Retroviral and Lentiviral Vector Productionmentioning

confidence: 99%

Tyrosine receptor kinase B is a drug target in astrocytomas

Xie

Ramkissoon

et al. 2016

Neuro-Oncology

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Background. Astrocytomas are the most common primary human brain tumors. Receptor tyrosine kinases (RTKs), including tyrosine receptor kinase B (TrkB, also known as tropomyosin-related kinase B; encoded by neurotrophic tyrosine kinase receptor type 2 [NTRK2]), are frequently mutated by rearrangement/fusion in high-grade and lowgrade astrocytomas. We found that activated TrkB can contribute to the development of astrocytoma and might serve as a therapeutic target in this tumor type. Methods. To identify RTKs capable of inducing astrocytoma formation, a library of human tyrosine kinases was screened for the ability to transform murine Ink4a −/− /Arf −/− astrocytes. Orthotopic allograft studies were conducted to evaluate the effects of RTKs on the development of astrocytoma. Since TrkB was identified as a driver of astrocytoma formation, the effect of the Trk inhibitors AZD1480 and RXDX-101 was assessed in astrocytoma cells expressing activated TrkB. RNA sequencing, real-time PCR, western blotting, and enzyme-linked immunosorbent assays were conducted to characterize NTRK2 in astrocytomas. Results. Activated TrkB cooperated with Ink4a/Arf loss to induce the formation of astrocytomas through a mechanism mediated by activation of signal transducer and activator of transcription 3 (STAT3). TrkB activation positively correlated with Ccl2 expression. TrkB-induced astrocytomas remained dependent on TrkB signaling for survival, highlighting a role of NTRK2 as an addictive oncogene. Furthermore, the QKI-NTRK2 fusion associated with human astrocytoma transformed Ink4a −/− /Arf −/− astrocytes, and this process was also mediated via STAT3 signaling. Conclusions. Our findings provide evidence that constitutively activated NTRK2 alleles, notably the human tumor-associated QKI-NTRK2 fusion, can cooperate with Ink4a/Arf loss to drive astrocytoma formation. Therefore, we propose NTRK2 as a potential therapeutic target in the subset of astrocytoma patients defined by QKI-NTRK2 fusion. Key words astrocytoma | CCL2 | NTRK2 | STAT3 | QKI-NTRK2

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Section: Plasmid Constructs Retroviral and Lentiviral Vector Productionmentioning

confidence: 99%

Tyrosine receptor kinase B is a drug target in astrocytomas

Xie

Ramkissoon

et al. 2016

Neuro-Oncology

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“…This phenotype stems from significant reductions in MEC proliferation resulting from a block in G1/S cell cycle transition and increase in the expression of cell cycle inhibitors, such as p27 and p21 [141]. The ability of C/EBPβ to promote MEC differentiation was further found to be mediated by the LAP1 isoform and dependent on cyclin D1 [142]. Cyclin D1 is important for HS-MEC proliferation in the normal mammary gland [31] and deletion of cyclin D1 completely ameliorates mammary ductal outgrowth in ERα-overexpressing mice [143], further linking C/EBPβ with hormonal signalling in the breast through HS-MECs.…”

Section: Caat/enhancer Binding Protein (C/ebpβ)mentioning

confidence: 99%

Hormone-Sensing Mammary Epithelial Progenitors: Emerging Identity and Hormonal Regulation

Tarulli

Laven-Law

Shakya

et al. 2015

J Mammary Gland Biol Neoplasia

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The hormone-sensing mammary epithelial cell (HS-MEC-expressing oestrogen receptor-alpha (ERα) and progesterone receptor (PGR)) is often represented as being terminally differentiated and lacking significant progenitor activity after puberty. Therefore while able to profoundly influence the proliferation and function of other MEC populations, HS-MECs are purported not to respond to sex hormone signals by engaging in significant cell proliferation during adulthood. This is a convenient and practical simplification that overshadows the sublime, and potentially critical, phenotypic plasticity found within the adult HS-MEC population. This concept is exemplified by the large proportion (~80 %) of human breast cancers expressing PGR and/or ERα, demonstrating that HS-MECs clearly proliferate in the context of breast cancer. Understanding how HS-MEC proliferation and differentiation is driven could be key to unraveling the mechanisms behind uncontrolled HS-MEC proliferation associated with ERα- and/or PGR-positive breast cancers. Herein we review evidence for the existence of a HS-MEC progenitor and the emerging plasticity of the HS-MEC population in general. This is followed by an analysis of hormones other than oestrogen and progesterone that are able to influence HS-MEC proliferation and differentiation: androgens, prolactin and transforming growth factor-beta1.

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“…Anoikis is a form of programmed cell death, which is induced by anchorage-dependent cells detaching from the surrounding extracellular matrix. Cyclin D1, which is overexpressed in many tumors, may also bind to LAP, an event that modulates the transcriptional function of LAP in mammary epithelial-cell differentiation [10,11].…”

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confidence: 99%

C/EBPβ LIP induces a tumor menagerie making it an oncogene

Luft¹

2014

J Mol Med

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Cyclin D1 and C/EBPβ LAP1 Operate in a Common Pathway To Promote Mammary Epithelial Cell Differentiation

Cited by 15 publications

References 39 publications

Tyrosine receptor kinase B is a drug target in astrocytomas

Tyrosine receptor kinase B is a drug target in astrocytomas

Hormone-Sensing Mammary Epithelial Progenitors: Emerging Identity and Hormonal Regulation

C/EBPβ LIP induces a tumor menagerie making it an oncogene

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