A gene has been identified that is expressed specifically in stromal cells surrounding invasive breast carcinomas. On the basis of its sequence, the product of this gene, named stromelysin-3, is a new member of the family of metalloproteinase enzymes which degrade the extracellular matrix. The suggestion is that stromelysin-3 is one of the stroma-derived factors that have long been postulated to play an important part in progression of epithelial malignancies.

GenoMEL, comprising major familial melanoma research groups from North America, Europe, Asia, and Australia has created the largest familial melanoma sample yet available to characterize mutations in the high-risk melanoma susceptibility genes CDKN2A/alternate reading frames (ARF), which encodes p16 and p14ARF, and CDK4 and to evaluate their relationship with pancreatic cancer (PC), neural system tumors (NST), and uveal melanoma (UM). This study included 466 families (2,137 patients) with at least three melanoma patients from 17 GenoMEL centers. Overall, 41% (n = 190) of families had mutations; most involved p16 (n = 178). Mutations in CDK4 (n = 5) and ARF (n = 7) occurred at similar frequencies (2-3%). There were striking differences in mutations across geographic locales. The proportion of families with the most frequent founder mutation(s) of each locale differed significantly across the seven regions (P = 0.0009). Single founder CDKN2A mutations were predominant in Sweden (p.R112_L113insR, 92% of family's mutations) and the Netherlands (c.225_243del19, 90% of family's mutations). France, Spain, and Italy had the same most frequent mutation (p.G101W). Similarly, Australia and United Kingdom had the same most common mutations (p.M53I, c.IVS2-105A>G, p.R24P, and p.L32P). As reported previously, there was a strong association between PC and CDKN2A mutations (P < 0.0001). This relationship differed by mutation. In contrast, there was little evidence for an association between CDKN2A mutations and NST (P = 0.52) or UM (P = 0.25). There was a marginally significant association between NST and ARF (P = 0.05). However, this particular evaluation had low power and requires confirmation. This GenoMEL study provides the most extensive characterization of mutations in high-risk melanoma susceptibility genes in families with three or more melanoma patients yet available. (Cancer Res 2006; 66(20): 9818-28)

Abstract. We have cloned from a mouse placenta cDNA library a mouse homologue of the human stromelysin-3 (ST3) eDNA, which codes for a putative matrix metalloproteinase expressed in breast carcinomas. The ST3 protein is well conserved between humans and mice, and the pattern of ST3 gene expression is similar in both species, and shows expression in the placenta, in the uterus, and during limb bud morphogenesis. We show that the ST3 gene can also be expressed in the normal mouse mammary gland. ST3 gene expression was not detected during mammary growth, neither in virgin nor in pregnant mice, but was specifically observed during postlactating involution of the gland, an apoptotic process associated with intense extracellular matrix remodeling. ST3 transcripts were found in fibroblasts immediately surrounding degenerative ducts, suggesting that ST3 gene expression may be associated with the basement membrane dissolution, which occurs during mammary gland involution. Since the ST3 gene is also specifically expressed in fibroblastic cells surrounding invasive neoplastic cells of breast carcinomas, we suggest that ST3 is implicated in extraceIlular matrix remodeling processes common to mammary apoptosis and breast cancer progression.