Abstract
The estrogen dependence of breast cancer has long been recognized; however, the role of 17beta-estradiol (E(2)) in cancer initiation was not known until we showed that it induces complete neoplastic transformation of the human breast epithelial cells MCF-10F. E(2) treatment of MCF-10F cells progressively induced high colony efficiency and loss of ductulogenesis in early transformed (trMCF) cells and invasiveness in Matrigel invasion chambers. The cells that crossed the chamber membrane were collected and identified as bsMCF; their subclones were designated bcMCF; and the cells harvested from carcinoma formation in severe combined immunodeficient mice were designated caMCF. These phenotypes correlated with gene dysregulation during the progression of the transformation. The highest number of dysregulated genes was observed in caMCF, being slightly lower in bcMCF, and lowest in trMCF. This order was consistent with the extent of chromosome aberrations (caMCF > bcMCF >>> trMCF). Chromosomal amplifications were found in 1p36.12-pter, 5q21.1-qter, and 13q21.31-qter. Losses of the complete chromosome 4 and 8p11.21-23.1 were found only in tumorigenic cells. In tumor-derived cell lines, additional losses were found in 3p12.1-14.1, 9p22.1-pter, and 18q11.21-qter. Functional profiling of dysregulated genes revealed progressive changes in the integrin signaling pathway, inhibition of apoptosis, acquisition of tumorigenic cell surface markers, and epithelial-mesenchymal transition. In tumorigenic cells, the levels of E-cadherin, epithelial membrane antigen, and various keratins were low and CD44E/CD24 were negative, whereas SNAI2, vimentin, S100A4, FN1, HRAS, transforming growth factor beta1, and CD44H were high. The phenotypic and genomic changes triggered by estrogen exposure that lead normal cells to tumorigenesis confirm the role of this steroid hormone in cancer initiation.
Highlights
Breast cancer is a malignancy whose dependence on ovarian function was shown by Beatson [1], who induced regression ofNote: Supplementary data for this article are available at Cancer Research Online, and http://www.fccc.edu/research/pid/russo-j/ index.html.Present address for Y
All the bcMCF subclones produced invasive poorly differentiated tumors in severe combined immunodeficient (SCID) mice with different morphologic phenotypes: spindle cell type, epithelial cell type, and with mix features of spindle and epithelial type. As it was previously reported, MCF-10F cells were seeded on Boyden chamber as control; cells that passed through the membrane were selected, expanded, and injected in SCID mice; these cells did not produce tumors [24]
Genomic aberrations progressively accumulated as the cells expressed more aggressive phenotypes in comparison with the nontumorigenic trMCF cells
Summary
The fact that ERa knockout mice expressing the Wnt-1 oncogene (ERKO/Wnt-1) develop mammary tumors in response to treatment with estrogen provides direct evidence that E2 may cause breast cancer through a genotoxic, non-ERa–mediated mechanism [5]. This postulate is further supported by the observation that when ovariectomized mice are supplemented with estrogen, they develop a higher tumor incidence with shorter latency time than control animals, even in the presence of the pure antiestrogen ICI-182,780. Experimental studies on estrogen metabolism [6], formation of DNA adducts [7], carcinogenicity [8, 9], mutagenicity [10], and cell transformation [11, 12] have supported the hypothesis that reaction of specific estrogen metabolites, namely catechol estrogen-3,4-quinones (CE3,4-Q) and, to a much lesser extent, CE-2,3-Q, can generate critical DNA mutations that initiate breast, prostate, and other cancers [13,14,15]
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