Oncotarget

Priority Research Papers:

c-Jun N-terminal kinase 2 prevents luminal cell commitment in normal mammary glands and tumors by inhibiting p53/Notch1 and breast cancer gene 1 expression

Michael A. Cantrell _, Nancy D. Ebelt, Adam D. Pfefferle, Charles M. Perou and Carla Lynn Van Den Berg

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Oncotarget. 2015; 6:11863-11881. https://doi.org/10.18632/oncotarget.3787

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Abstract

Michael A. Cantrell1,*, Nancy D. Ebelt1,*, Adam D. Pfefferle3,4, Charles M. Perou3,4,5, Carla Lynn Van Den Berg1,2

1Institute of Cellular & Molecular Biology, College of Pharmacy, University of Texas at Austin, Dell Pediatric Research Institute, Austin, TX 78723, USA

2Division of Pharmacology &Toxicology, College of Pharmacy, University of Texas at Austin, Dell Pediatric Research Institute, Austin, TX 78723, USA

3Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC 27599, USA

4Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC 27599, USA

5Department of Genetics, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC 27599, USA

*These authors have contributed equally to this work

Correspondence to:

Carla Lynn Van Den Berg, e-mail: carla.vandenberg@austin.utexas.edu

Keywords: breast cancer, JNK2, p53, Notch1, BRCA1

Received: March 13, 2015     Accepted: April 13, 2015     Published: April 25, 2015

ABSTRACT

Breast cancer is a heterogeneous disease with several subtypes carrying unique prognoses. Patients with differentiated luminal tumors experience better outcomes, while effective treatments are unavailable for poorly differentiated tumors, including the basal-like subtype. Mechanisms governing mammary tumor subtype generation could prove critical to developing better treatments. C-Jun N-terminal kinase 2 (JNK2) is important in mammary tumorigenesis and tumor progression. Using a variety of mouse models, human breast cancer cell lines and tumor expression data, studies herein support that JNK2 inhibits cell differentiation in normal and cancer-derived mammary cells. JNK2 prevents precocious pubertal mammary development and inhibits Notch-dependent expansion of luminal cell populations. Likewise, JNK2 suppresses luminal populations in a p53-competent Polyoma Middle T-antigen tumor model where jnk2 knockout causes p53-dependent upregulation of Notch1 transcription. In a p53 knockout model, JNK2 restricts luminal populations independently of Notch1, by suppressing Brca1 expression and promoting epithelial to mesenchymal transition. JNK2 also inhibits estrogen receptor (ER) expression and confers resistance to fulvestrant, an ER inhibitor, while stimulating tumor progression. These data suggest that therapies inhibiting JNK2 in breast cancer may promote tumor differentiation, improve endocrine therapy response, and inhibit metastasis.


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