Melanocytes use BRAF to activate the MAP kinase (MAPK) pathway because CRAF is inhibited by the cyclic AMP (cAMP) pathway in these cells. By contrast, melanomas harboring Ras mutations use CRAF to activate the MAPK pathway. We describe the molecular mechanism of Raf isoform switching and cAMP pathway disruption, which take place during melanocyte transformation. We show that overactivation of the MAPK pathway, induced by the oncogenic Ras in melanoma, induces constitutive phosphorylation of BRAF on Ser151 by ERK, which inhibits NRAS-BRAF interaction . We also demonstrate that melanoma cells have elevated cAMP phosphodiesterase activity owing to overexpression of the cAMP-specific phosphodiesterase-4 enzymes; this activity inhibits cAMP signaling and allows CRAF reactivation in these cells. Reactivating the cAMP pathway inhibits proliferation and induces apoptosis of Ras-mutated melanoma cells, suggesting a new therapeutic approach for treating melanomas harboring Ras mutations.

A second report of an intramural mesonephric adenocarcinoma of the uterus is presented. The histogenesis and clinicopathologic outcome of a surgically staged malignancy add to the insights and experience of this uncommon disorder.