title: 17-Beta-estradiol induces transformation and tumorigenesis in human breast epithelial cells.
abstract: Breast cancer is a malignancy whose dependence on estrogen exposure has long been recognized even though the mechanisms whereby estrogens cause cancer are not clearly understood. This work was performed to determine whether 17beta-estradiol (E2), the predominant circulating ovarian steroid, is carcinogenic in human breast epithelial cells and whether nonreceptor mechanisms are involved in the initiation of breast cancer. For this purpose, the effect of four 24 h alternate periods of 70 nM E2 treatment of the estrogen receptor alpha (ER-alpha) negative MCF-10F cell line on the in vitro expression of neoplastic transformation was evaluated. E2 treatment induced the expression of anchorage-independent growth, loss of ductulogenesis in collagen, invasiveness in Matrigel, and loss of 9p11-13. Only invasive cells that exhibited a 4p15.3-16 deletion were tumorigenic. Tumors were poorly differentiated ER-alpha and progesterone receptor-negative adenocarcinomas that expressed keratins, EMA, and E-cadherin. Tumors and tumor-derived cell lines exhibited loss of chromosome 4, deletions in chromosomes 3p12.3-13, 8p11.1-21, 9p21-qter, and 18q, and gains in 1p, and 5q15-qter. The induction of complete transformation of MCF-10F cells in vitro confirms the carcinogenicity of E2, supporting the concept that this hormone could act as an initiator of breast cancer in women. This model provides a unique system for understanding the genomic changes that intervene for leading normal cells to tumorigenesis and for testing the functional role of specific genomic events taking place during neoplastic transformation.
authors.affiliation: Breast Cancer Research Laboratory, Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, Pennsylvania 19111, USA. j_russo@fccc.edu
authors.forename: Jose
authors.initials: J
authors.lastname: Russo
authors.forename: Sandra V
authors.initials: SV
authors.lastname: Fernandez
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Russo
authors.forename: Rachael
authors.initials: R
authors.lastname: Fernbaugh
authors.forename: Fathima S
authors.initials: FS
authors.lastname: Sheriff
authors.forename: Hasan M
authors.initials: HM
authors.lastname: Lareef
authors.forename: James
authors.initials: J
authors.lastname: Garber
authors.forename: Irma H
authors.initials: IH
authors.lastname: Russo
mesh_terms: D001943:Breast Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced*; D002869:Chromosome Aberrations; D004847:Epithelial Cells / Q000473:pathology; D004958:Estradiol / Q000009:adverse effects*; D047628:Estrogen Receptor alpha / Q000172:deficiency; D005260:Female; D006801:Humans; D009361:Neoplasm Invasiveness / Q000473:pathology*; D011980:Receptors, Progesterone / Q000172:deficiency
chemical_list: D047628:Estrogen Receptor alpha; D011980:Receptors, Progesterone; D004958:Estradiol