Mohamed H. Lareef

Fox Chase Cancer Center

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José Russo

Fox Chase Cancer Center

Irma H. Russo

Fox Chase Cancer Center

Quivo Tahin

Universidade Estadual de Campinas (UNICAMP)

Maria Luiza S. Mello

Universidade Estadual de Campinas (UNICAMP)

Carolyn Slater

Fox Chase Cancer Center

Yun Hu

Southern Medical University

Dana Mihaila

Fox Chase Cancer Center

Benedicto C. Vidal

Universidade Estadual de Campinas (UNICAMP)

Binaifer Balsara

Kura Oncology (United States)

Benedicto de Campos Vidal

Universidade Estadual de Campinas (UNICAMP)

Cooperative Institutions

Fox Chase Cancer Center

Universidade Estadual de Campinas (UNICAMP)

University of Pennsylvania

Breast Cancer Research Foundation

Hospital de Clínicas da Unicamp

New York University

Technical University of Munich

Prevent Cancer Foundation

Philadelphia University

Temple University Health System

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Carcinogenicity of estrogens in human breast epithelial cells¹

Apmis (2001)

José Russo Yun Hu Quivo Tahin Dana Mihaila Carolyn Slater

Epidemiological and clinical evidences indicate that breast cancer risk is associated with prolonged ovarian function that results in elevated circulating levels of steroid hormones. Principal among these is estrogen, which is associated with two important risk factors, early onset of menarche and late menopause. However, up to now there is no direct experimental evidence that estrogens are responsible of the initiation of human breast cancer. We postulate that if estrogens are causative agents of this disease, they should elicit in human breast epithelial cells (HBEC) genomic alterations similar to those exhibited by human breast cancers, such as DNA amplification and loss of genetic material representing tumor suppressor genes. These effects could result from binding of the hormone to its nuclear receptors (ER) or from its metabolic activation to reactive metabolites. This hypothesis was tested by treating with the natural estrogen 17β‐estradiol (E 2 ) and the synthetic steroid diethylstilbestrol (DES) MCF‐10F cells, a HBEC line that is negative for ER. Cells treated with the chemical carcinogen benzo (a) pyrene (BP) served as a positive control of cell transformation. BP‐, E 2 ‐, and DES‐treated MCF‐10F cells showed increases in survival efficiency and colony efficiency in agar methocel, and loss of ductulogenic capacity in collagen gel. The largest colonies were formed by BP‐treated cells, becoming progressively smaller in DES‐ and E 2 ‐treated cells. The loss of ductulogenic capacity was maximal in BP‐, and less prominent in E2‐ and DES‐treated cells. Genomic analysis revealed that E 2 ‐ and DES‐treated cells exhibited loss of heterozygosity in chromosomes 3 and 11, at 3p21, 3p21–21.2, 3p21.1–14.2, and 3p14.2–14.1, and at 11q23.3 and 11q23.1–25 regions, respectively. It is noteworthy that these loci are also affected in breast lesions, such as ductal hyperplasia, carcinoma in situ, and invasive carcinoma. Our data are the first ones to demonstrate that estrogens induce in HBEC phenotypic changes indicative of cell transformation and that those changes are associated with significant genomic alterations that might unravel new pathways in the initiation of breast cancer.

10.1111/j.1600-0463.2001.tb00013.x

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Citations (37)

MMTV Env encodes an ITAM responsible for transformation of mammary epithelial cells in three-dimensional culture

The Journal of Experimental Medicine (2005)

Elad Katz Mohamed H. Lareef John C. Rassa Shannon Grande Leslie B. King

Expression of immunoreceptor tyrosine-based activation motif (ITAM)-containing signaling proteins is normally restricted to hematopoietic tissues. The basal activity of ITAM-containing proteins is mediated through negative regulation by coreceptors restricted to hematopoietic tissues. We have identified an ITAM signaling domain encoded within the env gene of murine mammary tumor virus (MMTV). Three-dimensional structures derived in vitro from murine cells stably transfected with MMTV env display a depolarized morphology in comparison with control mammary epithelial cells. This effect is abolished by Y>F substitution within the Env ITAM, as well as inhibitors of Syk and Src protein tyrosine kinases. Env-expressing cells bear hallmarks of cell transformation such as sensitivity to apoptosis induced by tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL) or TNFα, as well as down-regulation of E-cadherin and Keratin-18. Human normal mammary epithelial cells expressing MMTV Env also develop transformed phenotype, as typified by growth in soft agar and Matrigel invasion. These disruptions are abrogated by Y>F substitutions. We conclude that ITAM-dependent signals are generated through MMTV Env and trigger early hallmarks of transformation of mouse and human mammary epithelial cells. Therefore, these data suggest a heretofore unappreciated potential mechanism for the initiation of breast cancer and identify MMTV Env and ITAM-containing proteins in human breast tumors as probable oncoproteins.

Matrigel

Mammary tumor

10.1084/jem.20041471

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Citations (112)

Carcinogenicity of estrogens in human breast epithelial cells1

Apmis (2001)

José Russo Yun Hu Quivo Tahin Dana Mihaila Carolyn Slater

Epidemiological and clinical evidences indicate that breast cancer risk is associated with prolonged ovarian function that results in elevated circulating levels of steroid hormones. Principal among these is estrogen, which is associated with two important risk factors, early onset of menarche and late menopause. However, up to now there is no direct experimental evidence that estrogens are responsible of the initiation of human breast cancer. We postulate that if estrogens are causative agents of this disease, they should elicit in human breast epithelial cells (HBEC) genomic alterations similar to those exhibited by human breast cancers, such as DNA amplification and loss of genetic material representing tumor suppressor genes. These effects could result from binding of the hormone to its nuclear receptors (ER) or from its metabolic activation to reactive metabolites. This hypothesis was tested by treating with the natural estrogen 17β‐estradiol (E 2 ) and the synthetic steroid diethylstilbestrol (DES) MCF‐10F cells, a HBEC line that is negative for ER. Cells treated with the chemical carcinogen benzo (a) pyrene (BP) served as a positive control of cell transformation. BP‐, E 2 ‐, and DES‐treated MCF‐10F cells showed increases in survival efficiency and colony efficiency in agar methocel, and loss of ductulogenic capacity in collagen gel. The largest colonies were formed by BP‐treated cells, becoming progressively smaller in DES‐ and E 2 ‐treated cells. The loss of ductulogenic capacity was maximal in BP‐, and less prominent in E2‐ and DES‐treated cells. Genomic analysis revealed that E 2 ‐ and DES‐treated cells exhibited loss of heterozygosity in chromosomes 3 and 11, at 3p21, 3p21‐21.2, 3p21.1–14.2, and 3p14.2–14.1, and at 11q23.3 and 11q23.1–25 regions, respectively. It is noteworthy that these loci are also affected in breast lesions, such as ductal hyperplasia, carcinoma in situ, and invasive carcinoma. Our data are the first ones to demonstrate that estrogens induce in HBEC phenotypic changes indicative of cell transformation and that those changes are associated with significant genomic alterations that might unravel new pathways in the initiation of breast cancer.

10.1111/j.1600-0463.2001.tb05825.x

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Effect of human chorionic gonadotropin in the gene expression profile of MCF-7 cells

International Journal of Oncology (2004)

Shanchun Guo Irma H. Russo Mohamed H. Lareef José Russo

The preventive effect of human chorionic gonadotropin (hCG)-induced differentiation on experimental mammary carcinogenesis has been reported to be due to the inhibition of cell proliferation, increased DNA repair capabilities of the mammary epithelium, decreased binding of the carcinogen to the DNA and activation of programmed cell death genes leading to apoptosis. To further our understanding of the molecular pathway of the hCG action on mammary epithelial cells we have analyzed gene expression profiles of MCF-7 cells treated with hCG for 24, 48, and 96 h, using a DNA microarray consisting of 1176 genes. Comparison of expression between the treated and not treated cells enabled us to identify 48 genes that are affected by this hormone. Importantly, there is a cluster of genes that are overexpressed during the first 24 h and level off thereafter, whereas other genes are maximally expressed at 96 h of treatment. The results obtained in this study demonstrated that genes regulating cell proliferation, apoptosis, cell trafficking, and DNA repair are significantly affected by hCG in human breast cancer cells in vitro.

Human chorionic gonadotropin

10.3892/ijo.24.2.399

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RNA Relocation and Persistence of Nucleolus-Like Bodies at Mitosis in Benzo[a]Pyrene-Transformed Human Breast Epithelial Cells after Microcell-Mediated Transfer of Chromosomes 11 and 17

Analytical Cellular Pathology (2001)

Maria Luiza S. Mello Mohamed H. Lareef Benedicto C. Vidal José Russo

RNA relocation and the incidence of nucleolus‐like bodies accumulated during mitosis were studied cytochemically in benzo[a]pyrene (BP)‐transformed human breast epithelial MCF‐10F cells after microcell‐mediated transfer of normal chromosomes 11 and 17. The changes resulting from the transfer of these two chromosomes in tumorigenic MCF‐10F cells (BP1‐E cell line) were examined, since alterations in these chromosomes are involved in the expression of the transformed and tumorigenic phenotypes in the MCF‐10F cell series. In addition, the frequency of nucleolus‐like bodies decreases drastically with transformation and tumorigenicity in MCF‐10F cells, thus being conceivable that it would be affected in presence of normal chromosomes 11 or 17. The pattern of RNA relocation associated with the mitotic spindle did not vary in the cell lines analyzed. The introduction of chromosome 17 in BP1‐E cells either decreased or did not affect the frequency of persistent nucleolus‐like bodies. In contrast, in cells which received a normal chromosome 11, the frequency of nucleolus‐like bodies was closer to that of non‐transformed MCF‐10F cells. These results suggest that a normal chromosome 11 but not chromosome 17 contributes to the maintenance of an RNA surplus which accumulates in nucleolus‐like bodies during cell division of the human breast epithelial cells, at least in vitro. Some loci which were retained in the BP1‐E cells which received a normal chromosome 11 are probably involved with the control of RNA transcript production.

10.1155/2001/630121

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Citations (3)

NUCLEUS IMAGE PROPERTIES AND CELL DEATH IN MCF-10F CELLS GROWN ON SLIDE SUBSTRATES DIFFERING IN NATURE AND SIZE

In Vitro Cellular & Developmental Biology - Animal (2005)

Maria Luiza S. Mello Mohamed H. Lareef Adriana Brombini dos Santos J. Russo Vidal Bc

MCF-7

10.1290/0501004.1

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Citations (3)

Estrogen and its metabolites are carcinogenic agents in human breast epithelial cells

The Journal of Steroid Biochemistry and Molecular Biology (2003)

José Russo Mohamed H. Lareef Gabriela Balogh Shanchun Guo Irma H. Russo

10.1016/s0960-0760(03)00390-x

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Citations (252)

DNA content and chromatin texture of human breast epithelial cells transformed with 17-β-estradiol and the estrogen antagonist ICI 182,780 as assessed by image analysis

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis (2007)

Maria Luiza S. Mello Benedicto C. Vidal Irma H. Russo Mohamed H. Lareef José Russo

Neoplastic transformation

Estrogen receptor alpha

10.1016/j.mrfmmm.2006.08.013

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Citations (14)

Chromosome 17p13.2 transfer reverts transformation phenotypes and fas‐mediated apoptosis in breast epithelial cells

Molecular Carcinogenesis (2004)

Mohamed H. Lareef Quivo Tahin Joon Ho Song Irma H. Russo Dana Mihaila

Abstract Transformation of the human breast epithelial cells (HBEC) MCF‐10F with the carcinogen benz(a)pyrene (BP) into BP1‐E cells resulted in the loss of the chromosome 17 p13.2 locus (D17S796 marker) and formation of colonies in agar‐methocel (colony efficiency (CE)), loss of ductulogenic capacity in collagen matrix, and resistance to anti‐Fas monoclonal antibody (Mab)‐induced apoptosis. For testing the role of that specific region of chromosome 17 in the expression of transformation phenotypes, we transferred chromosome 17 from mouse fibroblast donors to BP1‐E cells. Chromosome 11 was used as negative control. After G418 selection, nine clones each were randomly selected from BP1‐E‐11 neo and BP1‐E‐17 neo hybrids, respectively, and tested for the presence of the donor chromosomes by fluorescent in situ hybridization and polymerase chain reaction‐based restriction fragment length polymorphism (PCR‐RFLP) analyses. Sensitivity to Fas Mab–induced apoptosis and evaluation of transformation phenotype expression were tested in MCF‐10F, BP1‐E, and nine BP1‐E‐11 neo and BP1‐E‐17 neo clones each. Six BP1‐E‐17 neo clones exhibited a reversion of transformation phenotypes and a dose dependent sensitivity to Fas Mab‐induced apoptosis, behaving similarly to MCF‐10F cells. All BP1‐E‐11 neo , and three BP1‐E‐17 neo cell clones, like BP1‐E cells, retained a high CE, loss of ductulogenic capacity, and were resistant to all Fas Mab doses tested. Genomic analysis revealed that those six BP1‐E‐17 neo clones that were Fas‐sensitive and reverted their transformed phenotypes had retained the 17p13.2 (D17S796 marker) region, whereas it was absent in all resistant clones, indicating that the expression of transformation phenotypes and the sensitivity of the cells to Fas‐mediated apoptosis were under the control of genes located in this region. © 2004 Wiley‐Liss, Inc.

10.1002/mc.20014

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Citations (1)

DNA content, chromatin texture and nuclear morphology in benzo[a]pyrene‐transformed human breast epithelial cells after microcell‐mediated transfer of chromosomes 11 and 17

Cytometry Part A (2003)

Maria Luiza S. Mello Benedicto de Campos Vidal Mohamed H. Lareef Yun Hu Xiaoqi Yang

A relation between the changes in DNA content and chromatin supra-organization and the expression of gradual steps of tumorigenesis has been assessed by image analysis in human breast epithelial cells (MCF-10F) treated with benzo[a]pyrene (BP) (cell lines BP1, BP1-E, BP1-Tras, and others).Because abnormal chromosomes 11 and 17 have been associated with neoplastic progression in BP-transformed MCF-10F cells, image analysis of Feulgen-stained tumorigenic BP1-E cells with the microcell-mediated chromosome transfer of normal chromosomes 11 and 17 was carried out.A tendency of DNA amount distribution and nuclear size restoration to values typical of non-transformed MCF-10F cells was demonstrated, especially after the transfer of chromosome 17. No reversion in chromatin texture was found after the transfer of chromosome 11 or 17.Although the presence of a normal chromosome 17 should be considered among the necessary steps for tumorigenic human breast epithelial cells to recover their normality, a more complex genome balance is required for the entire nuclear chromatin of these cells to recover its totally normal supra-organization and expression.

10.1002/cyto.a.10029

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Citations (12)