Loss of heterozygosity and microsatellite instability in epithelial hyperplasia of the breast

Kaneko, Mayumi; Arihiro, Koji; Takeshima, Yukio; Fujii, Satoshi; Inai, Kei

doi:10.1046/j.1359-4117.2002.01001.x

Cited by 21 publications

(7 citation statements)

References 20 publications

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“…[3][4][5][6][7][8][9][10][11][12][13] has been reported to exhibit imbalances in MCF-7 cells developing resistance to tamoxifen (65); region 8p11-21 encodes the frizzled-related gene FRP1/FRZB, which is turned off in 78% of breast carcinomas (66) and associated with androgen in prostate cancer (67). The loss of chromosome arm 18q is a common event in primary breast cancers (68 -72), ductal hyperplasia (73), and breast cancer cell lines (74), and is often interpreted as representing loss of one or more tumorsuppressor genes. The relevance of these losses in estrogen-induced cell transformation is that among the genes located in the q arm of chromosome 18 are two independent tumor suppressor loci in segment 18q21.1: one at SMAD4 and the other potentially at an enhancer of DCC or an unrelated novel gene (68,72).…”

Section: Discussionmentioning

confidence: 99%

17‐Beta‐Estradiol induces transformation and tumorigenesis in human breast epithelial cells

et al. 2006

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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.

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Section: Discussionmentioning

confidence: 99%

17‐Beta‐Estradiol induces transformation and tumorigenesis in human breast epithelial cells

et al. 2006

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“…Kaneko 31 demonstrated increasing frequencies of LOH in usual ductal hyperplasia from those without atypia through ADH.…”

Section: Molecular Alterations In Columnar Cell Lesions Dj Dabbs Et Almentioning

confidence: 98%

Molecular alterations in columnar cell lesions of the breast

et al. 2006

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Columnar cell lesions of the breast include a morphologic spectrum of simple columnar cell change, columnar cell hyperplasia, columnar cell hyperplasia with atypia and ductal carcinoma in situ of micropapillary/cribriform type. Invasive carcinomas of low grade are often seen in association with this spectrum. The biologic significance of these lesions that are commonly found on breast biopsies is unknown. Three cases of formalinfixed, paraffin-embedded breast tissues, each displaying the entire spectrum of columnar cell lesions through ductal carcinoma in situ and including foci of invasive carcinoma were microdissected at multiple sites to evaluate neoplasia progression. Minute tissue targets were microdissected (4-8/case) from unstained 4-lm thick recut paraffin sections and included non-neoplastic breast and sites of columnar cell change, hyperplasia, atypia, ductal carcinoma in situ and invasive carcinoma. Allelic imbalance for a broad panel of microsatellite markers in proximity to known tumor suppressor genes was quantitated using automated polymerase chain reaction/gel electrophoresis. Genomic loci evaluated 1p, 3p, 5q, 9p, 9q, 10q, 17p, 17q, 19q, 22q. The presence, topographic relationship and time course of mutational damage was correlated with columnar morphologic features. Detailed allelic imbalance information was obtained from each microdissection tissue target producing a detailed fingerprint of mutational damage in each case. Allelic damage was targeted predominately at 9q, 10q, 17p and 17q. Simple columnar cell change was without mutational changes and only present in one case of columnar cell hyperplasia. The remainder of the cases all show progressive accumulation of allelic damage in columnar cell changes with atypia, ductal carcinoma in situ and invasive carcinoma. The fractional mutation percentage increased progressively from columnar cell hyperplasia through invasive carcinoma. Low level of allelic imbalance was demonstrable in columnar cell lesions by the microdissection approach. A gradient of progressive mutational change could be delineated in each case manifesting allelic loss damage. Allelic loss damage appeared to preferentially target loci at 9q, 10q, 17p and 17q. The findings are consonant with the hypothesis that a select group of atypical columnar cell lesions are morphologic precursors to invasive carcinoma. Integrated molecular pathology analysis used here can help define the significance of columnar cell lesions and its role in breast cancer tumorigenesis on an individual patient basis.

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“…The region lost in chromosome 3 (p12.3-13) has been reported to exhibit imbalances in MCF-7 cells developing resistance to tamoxifen (63); the region 8p11-21 encodes the frizzled-related gene FRP1/FRZB, that is turned off in 78% of breast carcinomas (64), and associated with androgen in prostate cancer (65); the loss of chromosome arm 18q is a common event in primary breast cancers (60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70), ductal hyperplasia (71), and in breast cancer cell lines (72), and it is often interpreted as representing loss of one or more tumor-suppressor genes. The relevance of these losses in estrogen-induced cell transformation is that among the genes located in the q arm of chromosome 18 are two independent tumor-suppressor loci in segment 18q21.1, one at SMAD4 and the other potentially at an enhancer of DCC or an unrelated novel gene (66,70).…”

Section: Genomic Changes During the Tumorigenic Stage Of Malignant Trmentioning

confidence: 99%

The role of estrogen in the initiation of breast cancer

Russo

2006

The Journal of Steroid Biochemistry and Molecular Biology

487

302

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Estrogens are considered to play a major role in promoting the proliferation of both the normal and the neoplastic breast epithelium. Their role as breast carcinogens has long been suspected and recently confirmed by epidemiological studies. Three major mechanisms are postulated to be involved in their carcinogenic effects: stimulation of cellular proliferation through their receptor-mediated hormonal activity, direct genotoxic effects by increasing mutation rates through a cytochrome P450-mediated metabolic activation, and induction of aneuploidy. Recently it has been fully demonstrated that estrogens are carcinogenic in the human breast by testing in an experimental system the natural estrogen 17β-estradiol (E 2 ) by itself or its metabolites 2-hydroxy, 4-hydroxy, and 16-a-hydroxyestradiol (2-OH-E 2, 4-OH-E 2, and 16-α-OH E 2 ) respectively, by inducing neoplastic transformation of human breast epithelial cells (HBEC) MCF10F in vitro to a degree at least similar to that induced by the chemical carcinogen benz(a)pyrene (BP). Neither TAMOXYFEN (TAM) nor ICI-182,780 abrogated the transforming efficiency of estrogen or its metabolites. The E 2 induced expression of anchorage independent growth, loss of ductulogenesis in collagen, invasiveness in Matrigel, is associated with the loss of 9p11-13 and only invasive cells that exhibited a 4p15.3-16 deletion were tumorigenic. Tumors were poorly differentiated ER-α and progesterone receptor negative adenocarcinomas that expressed keratins, EMA and E-cadherin. The E 2 induced tumors and tumorderived 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 the human breast epithelial cell MCF-10F in vitro confirms the carcinogenicity of E 2 , 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. Keywordsestrogen; invasiveness; CGH; breast cancer 1.IntroductionBreast cancer is a malignancy whose dependence on ovarian function was first recognized through the regression of both advanced cancer (1) and metastatic disease (2) induced by oophorectomy in premenopausal women. Ulterior correlation of ovarian function with estrogen (1) To whom correspondence must be addressed: Jose Russo, M.D., F.C. A.P. Director, Breast Cancer Research Laboratory, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA, Phone: 215-728-4782, Fax: 215-728-2180, E-Mail: j_russo@fccc.edu Grant Numbers and Sources of support: This work was supported by the U.S. Army Medical and Research Materiel Command under grants DAMD17-00-1-0247 and DAMD17-03-1-0229.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a servi...

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Loss of heterozygosity and microsatellite instability in epithelial hyperplasia of the breast

Cited by 21 publications

References 20 publications

17‐Beta‐Estradiol induces transformation and tumorigenesis in human breast epithelial cells

17‐Beta‐Estradiol induces transformation and tumorigenesis in human breast epithelial cells

Molecular alterations in columnar cell lesions of the breast

The role of estrogen in the initiation of breast cancer

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