Selective Ablation of Glucocorticoid Receptor in Mouse Keratinocytes Increases Susceptibility to Skin Tumorigenesis Víctor Latorre, Lisa M. Sevilla,

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Selective Ablation of Glucocorticoid Receptor in Mouse Keratinocytes Increases Susceptibility to Skin Tumorigenesis Víctor Latorre, Lisa M. Sevilla, Ana Sanchis, Paloma Pérez Journal of Investigative Dermatology Volume 133, Issue 12, Pages 2771-2779 (December 2013) DOI: 10.1038/jid.2013.255 Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Increased sensitivity of GREKO mice to DMBA/PMA-induced skin tumorigenesis and altered histopathology of GREKO tumors. (a) Papilloma development evaluated in GREKO (n=20) and CO littermates (n=18) after a single dose of DMBA (23nmol) followed by 10μg PMA per mouse twice weekly for 19 weeks at the indicated times of promotion. (b) Mean tumor number (no.) per mouse (<2 and >2mm) determined at end point (18 male mice (8 CO and 10 GREKO) and 20 female mice (10 CO and 10 GREKO)). Average tumor numbers per mouse and statistical significance were determined; *P<0.05 and **P<0.01, n=56, Student’s t-test. (c–e, c′–e′) Representative hematoxylin and eosin (H&E) staining of 19-week papillomas collected from (c–e) CO and (c′–e′) GREKO mice (n=46 papillomas, 20 CO and 26 GREKO). Bars=100μm. *Indicates keratin pearls, discontinuous lines indicate diffuse epidermal (Ep)–stromal (St) border, and arrows indicate keratinocyte atypia (é). (f, f′) Immunostaining demonstrates delocalized expression of (f′) laminin A and (g) keratin 5 (K5)–positive keratinocytes invading the dermis (arrowheads) in GREKO tumors. (c–g) A total of 15 papillomas collected from 6 CO and 9 GREKO were analyzed. Bars (f, f′) =100μm; (g) =50μm. CO, control littermate; DMBA, 12-dimethylbenz(a) anthracene; GREKO, glucocorticoid receptor epidermal knockout; PMA, phorbol 12-myristate 13-acetate. Journal of Investigative Dermatology 2013 133, 2771-2779DOI: (10.1038/jid.2013.255) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Increased incidence of sebaceous adenomas and melanocytic foci (MFs) in glucocorticoid receptor epidermal knockout (GREKO) mice relative to control (CO) mice after high-dose 12-dimethylbenz(a) anthracene (DMBA) initiation and phorbol 12-myristate 13-acetate (PMA) promotion. (a) Skin tumor and (c) MF development evaluated in GREKO (n=10; 4 male mice and 6 female mice) and CO littermates (n=8; 3 male mice and 5 female mice) after a high dose of DMBA (390nmol), followed by 6μg PMA per mouse three times a week for 31 weeks at the indicated times of promotion. Total numbers of sebaceous tumors and MFs are represented. (b, b′) Representative hematoxylin and eosin (H&E) staining of 31-week sebaceous adenomas (n=18, 8 CO and 10 GREKO) and (d, d′) MFs (n=14, 6 CO and 8 GREKO) collected from each genotype. Note the greater extent of the MFs in GREKO relative to CO mice. Bar=100μm. Journal of Investigative Dermatology 2013 133, 2771-2779DOI: (10.1038/jid.2013.255) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Increased keratinocyte proliferation and inflammation in glucocorticoid receptor epidermal knockout (GREKO) mice skin papillomas. (a, a′) GREKO papillomas showed increased BrdU-positive keratinocytes and (b, b′) augmented Cyclin D1 (CycD1) expression; (c) negative control staining (slides incubated with secondary antibody (2nd Ab) alone). Bars=100μm. Basal (black arrow) and suprabasal (white arrows) keratinocytes are indicated. (d) Percentage and statistical significance (*P<0.05, n=13, Student’s t-test) of BrdU-positive basal keratinocytes. (e, e′) Hematoxylin and eosin (H&E) staining of GREKO papillomas showing marked immune infiltrates within the epidermis (white arrows) and the tumor stroma (black arrows) of GREKO mice. (f, f′) Immunohistochemistry (IH) for IL-6. (g) Negative control. Bars (e, e′)=100μm; (f, f′, g)=50μm. (a–g) A total of 13 papillomas collected from 5 control (CO) and 8 GREKO mice were analyzed. (h) Relative mRNA levels of Il6, Tnfa, and Il1b quantified by quantitative reverse-transcriptase–PCR (Q-RT-PCR) in GREKO and CO skin adjacent to tumors. Mean values± SD are shown (*P<0.05, n=7 skin samples collected from 3 CO and 4 GREKO, Student’s t-test). Journal of Investigative Dermatology 2013 133, 2771-2779DOI: (10.1038/jid.2013.255) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Altered keratinocyte differentiation and constitutively increased AKT and signal transducer and activator of transcription 3 (STAT3) activities in glucocorticoid receptor epidermal knockout (GREKO) mice skin papillomas. (a–c, a′–c′) Immunostaining for keratin 5 (K5), K10, and loricrin (LOR) shows abnormal differentiation of GREKO skin tumors relative to control (CO) mice. Arrowheads indicate local negative staining for K10 and loricrin. (d, e, d′, e′) Positive staining for K13 and focal reduced E-cadherin (E-CAD) immunostaining of GREKO tumors indicates early malignization. (f–h, f′–h′) Immunostaining for phosphorylated extracellular signal–regulated kinase (p-ERK), phosphorylated (p)-AKT, and STAT3 shows constitutively increased activities/nuclear localization in GREKO relative to CO epithelial tumors. White and black arrows denote suprabasal and basal staining, respectively. Bars=100μm. (a–h) A total of 11 papillomas collected from 4 CO and 7 GREKO were analyzed. (i, j) Representative immunoblot and quantification of three experiments show relative expression and ratios of phosphorylated and total ERK, AKT, and STAT3 in GREKO and CO papillomas. Actin, loading control. Mean values± SD are shown (*P<0.05, n=12 papillomas collected from 5 CO and 7 GREKO, Student’s t-test). Journal of Investigative Dermatology 2013 133, 2771-2779DOI: (10.1038/jid.2013.255) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Epidermal glucocorticoid receptor (GR) deficiency triggers a partial epithelial–mesenchymal transition in cultured keratinocytes. (a–f, a′–f′) Immunofluorescence staining for keratin 5 (K5), E-cadherin (E-cad), β-catenin (β-Cat), desmoplakin (DP), smooth muscle actin (SMA), and filamentous (F)-actin (phalloidin) in GR epidermal knockout (GREKO) versus control (CO) mice cells that were cultured in 0.35mM (a, a′) calcium or (b–f, b′–f′) incubated for 4hours with 1.2mM calcium before fixation. DAPI, 4',6-diamidino-2-phenylindole. In a and á, keratinocytes were grown for an additional 48hours after confluency. Bars=50μm. (g) Immunoblotting determined the relative expression of GR, E-cadherin, SMA, Snail, Slug, and K5 in GREKO and CO cultured keratinocytes. Tubulin, loading control. (h) Quantification of four independent experiments shows relative expression of the indicated proteins in GREKO compared with CO keratinocytes. Protein levels were arbitrarily set to 1 in CO cells. Mean values±SD are shown (*P<0.05 and **P<0.01, n=4, Student’s t-test). Journal of Investigative Dermatology 2013 133, 2771-2779DOI: (10.1038/jid.2013.255) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions