We found that while WT Fulvestrant supplier tumors do not express Twist , it is highly induced in K5-IKKa tumors obtained by both protocols of carcinogenesis . It is detected in the basal layer of the epidermis, where the K5 promoter directs the SU5416 VEGFR/PDGFR inhibitor expression of the IKKa transgene . As increased integrin-a6 expression is usually accompanied by increased proliferation , we next analyzed tumor cell proliferation, measured as BrdU incorporation, and found higher number of proliferating cells in the K5-IKKa tumors . However, the size of IKKa and WT tumors showed no significant differences; therefore, we examined the apoptosis in both types of tumors and found that WT papillomas exhibited low number of apoptotic cells . By contrast, the number of apoptotic cells in IKKa tumors was markedly higher . Nevertheless, the rate of proliferation is greater than that of apoptosis in transgenic tumors and these differences alone would not fully explain the similar size reached by both types of tumors. Panels E�CH�� in Figure 5 show staining of DMBA/TPA tumors although similar results were found in the Tg.AC tumors staining . Altogether these results suggest that skin tumors overexpressing IKKa in the basal layer of the epidermis have a malignant potential due at least in part to the induction of Twist expression and the suprabasal expression of integrin-a6. We have found that the overexpression of IKKa in the epidermis of K5-IKKa mice causes several molecular alterations, such as increased cyclin D1 expression, delocalized suprabasal integrin-a6 expression and downregulation of the tumor suppressor maspin. These proteins are important for cancer development and progression, suggesting that the skin of these Tg mice could develop more aggressive lesions when subjected to skin injuries than WT skin. We have proved that in fact, after applying proliferative stimuli in back skin, K5-IKKa mice develop epidermal atypia with loss of tissue architecture, being these pathological changes considered as preneoplastic signals. TPA also induces inflammation; the inflammatory response found both in WT and Tg mice following TPA treatment was similar, indicating that the alterations found in skin of Tg mice after TPA application are unlikely due to the proinflammatory activity of this agent. We have also found that in carcinogenesis assays Tg mice develop invasive tumors with higher malignant potential than the benign tumors developed in WT mice. The first anomaly detected in the epidermis of the Tg K5-IKKa mice was an enhanced proliferation of basal keratinocytes that seems to be the consequence of both enhanced cyclin D1 expression and increased integrin-a6 expression.