Tamoxifen induces TGF-β1 activity and apoptosis of human MCF-7 breast cancer cells in vitro

Chen, Hongmin; Tritton, Thomas R.; Kenny, Nicholas; Absher, Marlene; Chiu, Jen‐Fu

doi:10.1002/(sici)1097-4644(19960401)61:1<9::aid-jcb2>3.0.co;2-z

Cited by 89 publications

(41 citation statements)

References 23 publications

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“…TGF-␤ has also been shown to induce apoptosis in a variety of cancer cell lines including MCF-7 cells (65,66). Flow cytometric analysis demonstrated that PTGF-␤ does signal G 1 cell cycle arrest in MCF-7 cells, as evidenced by an increase in the G 1 /S ratio from 1.1 in untreated cells to 21.8 following AdPTGF-␤ treatment (Fig.…”

Section: Ptgf-␤ Overexpression Can Lead To the Induction Of P21mentioning

confidence: 87%

“…In MCF-7 cells, increased TGF-␤ levels have been associated with the induction of apoptosis in response to several anticancer agents, including tamoxifen (65). Recent evidence suggests that TGF-␤-mediated apoptotic signaling involves up-regulation of connective tissue growth factor, leading to reduced levels of Bcl-2 protein expression (81).…”

Section: Ptgf-␤ Overexpression Can Lead To the Induction Of P21mentioning

confidence: 99%

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Placental Transforming Growth Factor-β Is a Downstream Mediator of the Growth Arrest and Apoptotic Response of Tumor Cells to DNA Damage and p53 Overexpression

Li¹,

Wong²,

Ayed³

et al. 2000

Journal of Biological Chemistry

239

258

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The p53 tumor suppressor gene and members of the transforming growth factor-␤ (TGF-␤) superfamily play central roles in signaling cell cycle arrest and apoptosis (programmed cell death) in normal development and differentiation, as well as in carcinogenesis. Here we describe a distantly related member of the TGF-␤ superfamily, designated placental TGF-␤ (PTGF-␤), that is upregulated in response to both p53-dependent and -independent apoptotic signaling events arising from DNA damage in human breast cancer cells. PTGF-␤ is normally expressed in placenta and at lower levels in kidney, lung, pancreas, and muscle but could not be detected in any tumor cell line studied. The PTGF-␤ promoter is activated by p53 and contains two p53 binding site motifs. Functional studies demonstrated that one of these p53 binding sites is essential for p53-mediated PTGF-␤ promoter induction and specifically binds recombinant p53 in gel mobility shift assays. PTGF-␤ overexpression from a recombinant adenoviral vector (AdPTGF-␤) led to an 80% reduction in MDA-MB-468 breast cancer cell viability and a 50 -60% reduction in other human breast cancer cell lines studied, including MCF-7 cells, which are resistant to growth inhibition by recombinant wild-type p53. Like p53, PTGF-␤ overexpression was seen to induce both G 1 cell cycle arrest and apoptosis in breast tumor cells. These results provide the first evidence for a direct functional link between p53 and the TGF-␤ superfamily and implicate PTGF-␤ as an important intercellular mediator of p53 function and the cytostatic effects of radiation and chemotherapeutic cancer agents.

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Section: Ptgf-␤ Overexpression Can Lead To the Induction Of P21mentioning

confidence: 87%

Section: Ptgf-␤ Overexpression Can Lead To the Induction Of P21mentioning

confidence: 99%

Placental Transforming Growth Factor-β Is a Downstream Mediator of the Growth Arrest and Apoptotic Response of Tumor Cells to DNA Damage and p53 Overexpression

Li¹,

Wong²,

Ayed³

et al. 2000

Journal of Biological Chemistry

239

258

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“…The biochemical hallmark of apoptosis is internucleosomal DNA cleavage (38)(39)(40), and it can be detected by the TUNEL assay or by conventional gel electrophoresis (41). In this report, we have presented data to demonstrate that the hPRLR antagonist, hPRL-G129R, is able to induce apoptosis by DNA fragmentation in multiple human breast cancer cell lines.…”

Section: Discussionmentioning

confidence: 96%

Rational Design of Human Prolactin Receptor Antagonists for Breast Cancer Therapy

Chen¹

2003

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302, and to the Office of Management and Budget,, Washington, DC 20503 AGENCY USE ONLY (Leave blank)2. REPORT DATE October 2000 REPORT TYPE AND DATES COVEREDAnnual (15 Sep 99 -14 Sep 00) TITLE AND SUBTITLE Rational Design of Human Prolactin Receptor Antagonists for Breast Cancer Therapy AUTHOR(S)Wen Y. Chen, Ph.D. There were three tasks proposed for the first year of this project. All three tasks have been accomplished. FUNDING NUMBERSWe have cloned and confirmed by sequencing the cDNAs encoding hPRL, hPRL-G129R and hPRL-BP (task 1). All three cDNAs have been transfected into mouse L cells and stable mouse L cells have been established (task 2).We have also maintaining 12 human cancer cell lines purchased from ATCC(task 3). In addition, we have demonstrated that hPRL-G129R is able to inhibit breast cancer cell proliferation via induction of apoptosis (Clinical Cancer Research, 5:3583-3593, 1999). We are confident that the project will go on as proposed in years two and three. SUBJECT TERMS IntroductionHuman breast cancer is the most predominant malignancy with the highest mortality rate in women from western society. Many risk factors have been identified for this disease. Several lines of evidence strongly linked human prolactin (hPRL) to breast carcinogenesis. In this proposal, two novel approaches have been designed to generate hPRL receptor specific antagonists. First approach is to adopt a sitedirected mutagenesis strategy by which hGH receptor antagonist, hGH-G120R, was discovered, to produce a mutated hPRL, hPRL-G129R, and use it as hPRL receptor blocker. The other approach is to design and produce a soluble form of extra-cellular domain of hPRL receptor namely hPRL binding protein (hPRL-BP), and use it to sequester autocrine/paracrine effects of hPRL. After cloning of hPRL and hPRL-BP cDNAs, mutation will be made in hPRL cDNA to generate hPRL-G129R. Human PRL, hPRL-G129R and hPRL-BP cDNAs will then be used to establish stably transfected mouse L cells. The proteins produced from stably transfected mouse L cells will be purified and used to test its bioactivities in ten different human breast cancer cell lines and two non-breast origin human cancer cell lines (as controls) for receptor binding, inhibition of phosphorylation of the STAT 5 protein induced by hPRL (as an indicator for intracellular signaling), and inhibition of human breast cancer cell proliferation. We hope that these two novel approaches will ultimately result ...

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“…TGF is an autocrine regulator of cell growth in MCF-7 cells, and its secretion is stimulated by TAM (Perry et al 1995, Chen et al 1996, Knabbe et al 2000. Regulation of TGF secretion by TAM+AT was studied using specific ELISAs to quantitate medium TGF content.…”

Section: Modulation Of Tgf By At/tammentioning

confidence: 99%

“…Both retinoids and anti-estrogens block cell cycle progression at G 0 G 1 , and both agents reduce the hyperphosphorylated form of the retinoblastoma protein (pRb), indicating an important convergence point for their action (Wilcken et al 1996). Both retinoids and anti-estrogens downregulate Bcl-2 gene and protein expression (Wang & Phang 1995, Zhang et al 1999 and stimulate apoptosis in breast cancer cells (Perry et al 1995, Chen et al 1996, Liu et al 1996, Toma et al 1997. These similarities raise the possibility that synergism involves shared anti-proliferative pathways.…”

Section: Introductionmentioning

confidence: 99%

All trans-retinoic acid acts synergistically with hydroxytamoxifen and transforming-growth factor β to stimulate apoptosis in MCF-7 breast cancer cells

Danforth¹

2004

Journal of Endocrinology

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The anti-estrogen 4-hydroxytamoxifen (TAM) and vitamin A-related compounds, the retinoids, in combination act synergistically to inhibit growth of breast cancer cells in vitro and in vivo. To clarify the mechanism of this synergism, the effect of TAM and all trans-retinoic acid (AT) on proliferation of MCF-7 breast cancer cells was studied in vitro. TAM and AT acted synergistically to cause a time-dependent and dose-dependent inhibition of MCF-7 cell growth. In a temporally related manner, TAM+AT acted synergistically to downregulate Bcl-2 mRNA and Bcl-2 protein expression, and to stimulate apoptosis. TAM and AT each blocked cell cycle progression throughout 7 days of treatment but without any synergistic or additive effect on this process, indicating a selective synergism for apoptosis.The negative growth factor-transforming growth factor (TGF ) is secreted by these cells and was studied as a potential mediator of the synergistic effects of TAM+AT on apoptosis. TAM+AT acted synergistically to induce a fivefold increase in TGF 1 secretion over 72 h. TGF 1 alone had no apoptotic effects on these cells; however, TGF 1 in combination with AT acted synergistically to inhibit growth, to downregulate Bcl-2 mRNA and Bcl-2 protein expression, and to stimulate apoptosis of these cells in a manner comparable with that noted for TAM+AT. The synergism of both TAM+AT and TGF 1+AT for apoptosis was suppressed by estradiol. Co-incubation of TAM+AT with anti-TGF antibody did not block downregulation of Bcl-2 protein expression or stimulation of apoptosis. The synergistic effects of TAM+AT on apoptosis therefore occur independently of TGF , although TGF may interact with AT in a novel manner to provide another important anti-proliferative mechanism for breast cancer cells.

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Tamoxifen induces TGF-β1 activity and apoptosis of human MCF-7 breast cancer cells in vitro

Cited by 89 publications

References 23 publications

Placental Transforming Growth Factor-β Is a Downstream Mediator of the Growth Arrest and Apoptotic Response of Tumor Cells to DNA Damage and p53 Overexpression

Placental Transforming Growth Factor-β Is a Downstream Mediator of the Growth Arrest and Apoptotic Response of Tumor Cells to DNA Damage and p53 Overexpression

Rational Design of Human Prolactin Receptor Antagonists for Breast Cancer Therapy

All trans-retinoic acid acts synergistically with hydroxytamoxifen and transforming-growth factor β to stimulate apoptosis in MCF-7 breast cancer cells

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