NEW WORK IN EXPERIMENTAL DERMATOLOGY

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Cycling up the epidermis: reconciling 100 years of debate.

 Alberto Gandarillas^1,2,* and Ana Freije¹

Experimental Dermatology.
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http://onlinelibrary.wiley.com/doi/10.1111/exd.12287/abstract

ABSTRACT

There is likely general consensus within the skin research community that cell cycle control is critical to epidermal homeostasis and disease. The current predominant model proposes that keratinocytes switch off DNA replication and undergo cell cycle and cell growth arrest as they initiate terminal differentiation. However, this model cannot explain key physiological features of the skin, mainly why squamous differentiation prevails over proliferation in benign hyperproliferative disorders. In recent years we have proposed an alternative model that involves mitotic slippage and endoreplication. This new model is controversial and has encountered resistance within the field. However, looking back at history, the epidermal cell cycle has been a matter of controversy and debate for around 100 years now. The accumulated data are confusing and contradictory. Our present model can explain and reconcile both old and new paradoxical observations. Here we explain and discuss the endoreplicative cell cycle, the evidence for and against its existence in human epidermis and the important implications for skin homeostasis and disease. We show that regardless of the strengths or weaknesses of the Endoreplication Model, the existing evidence in support of the Cell Cycle Arrest Model is very weak.

Keywords: DNA damage – MYC - endocycles – cancer –carcinoma

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NEW WORK IN MOLECULAR CANCER

We collaborate with Marisa Martín-Faraldo and Marina Glukhova on the role of MYC in the mammary gland (Moumen et al, 2012; Moumen et al, 2013).

Mol Cancer. 2013 Oct 30;12(1):132. [Epub ahead of print]

WHOLE TEXT IN http://www.molecular-cancer.com/content/12/1/132

Myc is required for beta-catenin-mediated mammary stem cell amplification and tumorigenesis.

Moumen M, Chiche A, Decraene C, Petit V, Gandarillas A, Deugnier MA, Glukhova MA, Faraldo MM.

Abstract

BACKGROUND:

Basal-like breast cancer is a heterogeneous disease characterized by the expression of basal cell markers, no estrogen or progesterone receptor expression and a lack of HER2 overexpression. Recent studies have linked activation of the Wnt/beta-catenin pathway, and its downstream target, Myc, to basal-like breast cancer. Transgenic mice K5DeltaNbetacat previously generated by our team present a constitutive activation of Wnt/beta-catenin signaling in the basal myoepithelial cell layer, resulting in focal mammary hyperplasias that progress to invasive carcinomas. Mammary lesions developed by K5DeltaNbetacat mice consist essentially of basal epithelial cells that, in contrast to mammary myoepithelium, do not express smooth muscle markers.

METHODS:

Microarray analysis was used to compare K5DeltaNbetacat mouse tumors to human breast tumors, mammary cancer cell lines and the tumors developed in other mouse models. Cre-Lox approach was employed to delete Myc from the mammary basal cell layer of K5DeltaNbetacat mice. Stem cell amplification in K5DeltaNbetacat mouse mammary epithelium was assessed with 3D-culture and transplantation assays.

RESULTS:

Histological and microarray analyses of the mammary lesions of K5DeltaNbetacat females revealed their high similarity to a subset of basal-like human breast tumors with squamous differentiation. As in human basal-like carcinomas, the Myc pathway appeared to be activated in the mammary lesions of K5DeltaNbetacat mice. We found that a basal cell population with stem/progenitor characteristics was amplified in K5DeltaNbetacat mouse preneoplastic glands. Finally, the deletion of Myc from the mammary basal layer of K5DeltaNbetacat mice not only abolished the regenerative capacity of basal epithelial cells, but, in addition, completely prevented the tumorigenesis.

CONCLUSIONS:

These results strongly indicate that beta-catenin-induced stem cell amplification and tumorigenesis rely ultimately on the Myc pathway activation and reinforce the hypothesis that basal stem/progenitor cells may be at the origin of a subset of basal-like breast tumors.

PMID: 24171719 [PubMed - as supplied by publisher] Free full text