The elucidation of molecular alterations that occur during human breast cancer progression may contribute to the development of preventative strategies. Using in situ hybridizations on a cohort of 94 biopsy lesions, quantitatively increased cyclin D mRNA expression levels were observed in only 18% of benign lesions, which confer no or slightly increased breast cancer risk, and 18% of premalignant atypical ductal hyperplasias, which confer a four to fivefold increase in breast cancer risk. The transition to carcinoma was accompanied by frequent cyclin D mRNA overexpression in 76% of low-grade ductal carcinomas in situ, 87% of higher grade comedo ductal carcinomas in situ and 83% of infiltrating ductal breast carcinomas. The data identify a molecular event that may separate benign and premalignant human breast lesions from any form of breast carcinoma.

Tumor metastasis is a major cause of death for cancer patients. This review proposes that the final steps in the development of a distant metastasis may be the most productive targets for clinical development. It cannot be guaranteed that, in "metastasis-free" patients, tumor cells have not invaded out of the primary lesion, intravasated and extravasated from the circulatory system, and are sitting at distant sites as occult micrometastases. The remaining processes involved in outgrowth at metastatic sites, colonization and angiogenesis, are reviewed. Colonization is thought to be accomplished by clonally dominant cell populations through progressive independence from exogenous growth factors, production of growth factors, and stimulatory proliferative responses to traditionally inhibitory cytokines. Therapeutic efforts aimed at interrupting the switch in tumor cell responsiveness to cytokines, rather than to any one specific cytokine, may be most successful at inhibiting metastatic colonization. Angiogenesis has been demonstrated to be directly or indirectly induced by a plethora of cytokines. Partial suppression of neovascularization can be achieved in tissue culture and animal models using various natural and pharmaceutical angiostatic agents. However, as with clonal dominance, such agents must be able to suppress the redundant effects of angiogenesis-promoting factors. This review discusses the current literature on colonization and angiogenesis, emphasizing its underlying mechanisms and potential therapeutic applications.

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In an attempt to isolate candidate genes for autosomal dominant polycystic kidney disease, a number of CpG-rich islands have been identified from a region defined genetically as the site of disease mutations. Genomic fragments adjacent to one of these islands were used to isolate cDNAs from both HeLa cells and cultured cystic epithelium that encode a 155-amino acid peptide having four putative transmembrane domains. The corresponding transcript was found in all tissues tested but was most abundant in brain and kidney. Potential control response elements were identified in the genomic region 5' to the initiation codon. The deduced amino acid sequence has 93% similarity to the 16-kDa proteolipid component that is believed to be part of the proton channel of the vacuolar H+-ATPase. Possible roles for a mutated proton channel in the pathogenesis of cystic disease were considered. However, sequencing of cDNAs corresponding to both alleles of an affected individual revealed no differences in the deduced amino acid sequence. Moreover, transcript size and abundance were not altered in cystic kidney.