Abstract 2366: Role of MKP1 in skin carcinogenesis

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Dual-specificity phosphatase type 1 (DUSP1/MKP1), is a member of the dual-specific family of phosphatases that can dephosphorylate and inactivate all three major Mitogen-Activated Protein Kinases (MAPKs), including Extracellular Regulated Kinase (ERK1/2), c-Jun N-Terminal Kinase (JNK1/2), and p38. MKP1 is a nuclear protein whose expression is regulated by mitogenic, inflammatory and DNA-damage stimuli. Basal levels of MKP1 are usually low in normal cells, however high levels of the protein have been found in several human tumours such as ovarian, breast, prostate and lung. Amplification and mutation of Ha-Ras correlates with the malignancy of tumours that appears in chemically-induced mouse skin and additionally, an increase in Ha-Ras levels induces JNK1/2 and ERK1/2 activity, known substrates of MKP1, however, there is no evidence in the literature of a relationship between MKP1 and skin cancer. The objective of this study was to investigate the role of MKP1 in carcinogenesis and tumor development in carcinogen-induced skin cancer. MKP1 wild-type (mkp1+/+) and MKP1 knock-out (mkp1-/-) mice were subjected to the standard two-stage skin carcinogenesis protocol using 7, 12-dimethylbenz(a)anthraacene (DMBA) as the initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as the promoter. We observed a significant decrease in both papilloma incidence and papilloma multiplicity in mkp1+/+ mice undergoing two-stage skin carcinogenesis relative to mkp1-/- littermates. Morphological evaluation of skin lesions from mkp1+/+ and mkp1-/- mice revealed a significant reduction in both tumour incidence and tumour multiplicity in mkp1+/+ mice relative to mkp1-/- littermates. No differences were found between mkp1+/+ and mkp1-/- skin hyperplasia following TPA challenge, but we observed reduced bromodeoxyuridine (BrdUrd) incorporation in mkp1+/+ epidermis compared with mkp1-/- epidermis. Targeted disruption of MKP1 gene led to a slight increase in ERK1/2 protein in mkp1-/- mice, whereas p38 and JNK1/2 proteins were expressed at similar levels in the epidermis of mkp1+/+ and mkp1-/- mice. We examined the effect of MKP1 deficiency on ERK1/2 activation and we observed that TPA-mediated activation of ERK1/2 was diminished in mkp1+/+ epidermis compared with mkp1-/- epidermis. Finally, we have also observed a marked reduction in MKP1 expression levels in human basal (BCC) and squamous cell carcinoma (SCC) in relation to normal skin. In contrast to the results found in other tumor types as lung cancer, our data provide a strong evidence for MKP1 having a role in the tumorogenesis and development of skin cancer by attenuating epidermal response to tumour promotion, and ultimately, two-stage skin carcinogenesis, very likely by impairing the activation of the ERK1/2 pathway, critically linked to control of cell proliferation and skin tumorigenesis. Supported by PI081485 and P09/1988 and by an unrestricted educational grant from Fundacion Mutua Madrilena 2007-0444 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2366. doi:1538-7445.AM2012-2366