Abstract
AbstractIn order to determine what is the role of genomic alterations in neoplasia, it is necessary to verify what is their function at each one of the various stages of breast cancer progression, which initiates as ductal hyperplasia, progressing to atypical ductal hyperplasia, carcinoma in situ, and invasive and metastatic adenocarcinoma. These studies are hindered by the fact that these stages are not always present in a single patient, or in a sequential manner, or when present the available material might be insufficient or inadequate for performing genetic manipulation for testing their functional role. These disadvantages have been overcome by utilizing an in vitro model of cell transformation, the spontaneously immortalized human breast epithelial cell line (HBEC) MCF‐ 10F, which upon treatment with the chemical carcinogens benzo(a)pyrene (BP) or 7,12‐dimethyl‐benz(a)anthracene (DMBA) expresses in a sequential fashion all the phenotypes indicative of neoplastic transformation, i.e., increased survival in agar, formation of colonies in agar methocel, invasiveness in a matrigel in vitro system, and tumorigenesis in severe combined immunodeficient (SCID) mice. The immortalization of MCF‐1 OF cells is associated with the presence of a point mutation in exon 7 of the tumor suppressor gene p53. Carcinogen‐induced transformation was manifested as colony formation in agar methocel and anchorage independence, which were associated with loss of heterozygosity (LOH) and point mutations in codons 12 and 61 of c‐Ha‐ras gene. Other oncogenes involved in this early stage were c‐neu, c‐myc, and int‐2. The expression of the tumorigenic phenotype was associated with LOH in the telomeric portion of chromosome 17 and overexpression of the mdm2 gene. This in vitro system provides all of the sequential steps to neoplastic transformation in a reproducible manner, thus providing a paradigm for clarifying the role of the genetic alterations in tumor initiation and progression. © 1995 Wiley‐Liss, Inc.
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