Imperial College London

ProfessorSimakAli

Faculty of MedicineDepartment of Surgery & Cancer

Professor of Molecular Endocrine Oncology
 
 
 
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Contact

 

+44 (0)20 7594 2811simak.ali

 
 
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Location

 

133ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

154 results found

Martin L-A, Farmer I, Johnston SRD, Ali S, Dowsett Met al., 2005, Elevated ERK1/ERK2/estrogen receptor cross-talk enhances estrogen-mediated signaling during long-term estrogen deprivation., Endocr Relat Cancer, Vol: 12 Suppl 1, Pages: S75-S84, ISSN: 1351-0088

The knowledge that steroids play a pivotal role in the development of breast cancer has been exploited clinically by the development of endocrine treatments. These have sought to perturb the steroid hormone environment of the tumour cells, predominately by withdrawal or antagonism of oestrogen. Unfortunately, the beneficial actions of existing endocrine treatments are attenuated by the ability of tumours to circumvent the need for steroid hormones, whilst in most cases, retaining the nuclear steroid receptors. The mechanisms involved in resistance to estrogen deprivation are of major clinical relevance for optimal treatment of breast cancer patients and the development of new therapeutic regimes. We have shown that long-term culture of MCF7 cells in medium depleted of oestrogen (LTED) results in hypersensitivity to oestradiol (E2) coinciding with elevated levels of both ERalpha phosphorylated on Ser(118) and ERK1/ERK2. Our data suggest elevated ERK1/ERK2 activity results wholly or in part from enhanced ERBB2 expression in the LTED cells. These cells showed greater sensitivity to the tyrosine kinase inhibitor ZD1839 in both ERalpha-mediated transcription and growth assays compared with the wt-MCF7. Similarly the MEK inhibitor U0126 decreased basal ERalpha-mediated transcription and proliferation in the LTED cells by 50% and reduced their sensitivity to the proliferative effects of E2 10-fold, whilst having no effect on the wild type (wt). However, complete suppression of ERK1/ERK2 activity in the LTED cells did not inhibit ERalpha Ser(118) phosphorylation suggesting that the cells remained ligand-dependent. This was further confirmed by the increased sensitivity of the LTED cells to the growth suppressive effects of ICI 182,780 and suggested that the LTED cells remained wholly or partially dependent on oestrogen receptor (ER)/oestrogen responsive elements directed growth. These findings suggest that treatments targeted at growth factor signalling pathways may be usef

Journal article

Polychronis A, Sinnett HD, Hadjiminas D, Singhal H, Monsi JL, Shivapatham D, Shousha S, Jiang J, Peston D, Barrett N, Vigushin D, Morrison K, Beresford E, Ali S, Slade MJ, Coombes RCet al., 2005, Preoperative gefitinib versus gefitinib and anastrozole in postmenopausal patients with oestrogen-receptor positive and epidermal-growth-factor-receptor-positive primary breast cancer: A double-blind placebo-controlled phase II randomised trial, LANCET ONCOLOGY, Vol: 6, Pages: 383-391, ISSN: 1470-2045

Journal article

Buluwela L, Pike J, Mazhar D, Kamalati T, Hart SM, Al-Jehani R, Yahaya H, Patel N, Sarwarl N, Heathcote DA, Schwickerath O, Phoenix F, Hill R, Aboagye E, Shousha S, Waxman J, Lemoine NR, Zelent A, Coombes RC, Ali Set al., 2005, Inhibiting estrogen responses in breast cancer cells using a fusion protein encoding estrogen receptor-alpha and the transcriptional repressor PLZF (vol 12, pg 452, 2005), GENE THERAPY, Vol: 12, Pages: 862-862, ISSN: 0969-7128

Journal article

Buluwela L, Pike J, Mazhar D, Kamalati T, Hart SM, Al-Jehani R, Yahaya H, Patel N, Sarwar N, Heathcote DA, Schwickerath O, Phoenix F, Hill R, Aboagye E, Shousha S, Waxman J, Lemoine NR, Zelent A, Coombes RC, Ali Set al., 2005, Inhibiting estrogen responses in breast cancer cells using a fusion protein encoding estrogen receptor-alpha and the transcriptional repressor PLZF (vol 12, pg 452, 2005), GENE THERAPY, Vol: 12, Pages: 552-552, ISSN: 0969-7128

Journal article

Buluwela L, Pike J, Mazhar D, Kamalati T, Hart SM, Al-Jehani R, Yahaya H, Patel N, Sarwarl N, Heathcote DA, Schwickerath O, Phoenix F, Hill R, Aboagye E, Shousha S, Waxman J, Lemoine NR, Zelent A, Coombes RC, Ali Set al., 2005, Inhibiting estrogen responses in breast cancer cells using a fusion protein encoding estrogen receptor-alpha and the transcriptional repressor PLZF, GENE THERAPY, Vol: 12, Pages: 452-460, ISSN: 0969-7128

Journal article

Varshochi R, Halim F, Sunters A, Alao JP, Madureira PA, Hart SM, Ali S, Vigushin DM, Coombes RC, Lam EWFet al., 2005, ICI182,780 induces p21(Waf1) gene transcription through releasing histone deacetylase 1 and estrogen receptor alpha from Sp1 sites to induce cell cycle arrest in MCF-7 breast cancer cell line, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 280, Pages: 3185-3196, ISSN: 0021-9258

Journal article

Lucey MJ, Chen DS, Lopez-Garcia J, Hart SM, Phoenix F, Al-Jehani R, Alao JP, White R, Kindle KB, Losson R, Chambon P, Parker MG, Schar P, Heery DM, Buluwela L, Ali Set al., 2005, T : G mismatch-specific thymine-DNA glycosylase (TDG) as a coregulator of transcription interacts with SRC1 family members through a novel tyrosine repeat motif, NUCLEIC ACIDS RESEARCH, Vol: 33, Pages: 6393-6404, ISSN: 0305-1048

Journal article

Alao JP, Lam EWF, Ali S, Buluwela L, Bordogna W, Lockey P, Varshochi R, Stavropoulou AV, Coombes RC, Vigushin DMet al., 2004, Histone deacetylase inhibitor trichostatin a represses estrogen receptor alpha-dependent transcription and promotes proteasomal degradation of cyclin D1 in human breast carcinoma cell lines, CLINICAL CANCER RESEARCH, Vol: 10, Pages: 8094-8104, ISSN: 1078-0432

Journal article

Pike J, Holmes D, Kamalati T, Davies D, Tolhurst R, Mazhar D, Fishpool S, al-Jehani R, Waxman J, Zelent A, Lemoine NR, Ali S, Buluwela Let al., 2004, Silencing of androgen-regulated genes using a fusion of AR with the PLZF transcriptional repressor, ONCOGENE, Vol: 23, Pages: 7561-7570, ISSN: 0950-9232

Journal article

HART STEPHEN, ALI SIMAK, PUFONG BORIS T, PORTER ANDREW CG, BULUWELA LAKI, VAINIKKA SATU, JENKINSON JOHN D, KANDA PATRICKet al., 2004, Control of gene expression using a complex of an oligonucleotide and a regulatory peptide

A method for suppressing the expression of a selected gene in a cell the method comprising introducing into the cell a molecule comprising (1) a nucleic acid binding portion which binds to a site or associated with the selected gene which site is present in a genome and (2) an expression repressor portion, wherein the nucleic acid binding portion comprises an oligonucleotide or oligonucleotide mimic or analogue, and wherein the repressor portion comprises a polypeptide or peptidomimetic. Molecules for use in the methods of the invention are provided. The repressor may be a portion of a histone deacetylase or DNA methylase or polypeptide capable of recruiting a histone deacetylase or DNA methylase.

Journal article

Bhat-Nakshatri P, Campbell RA, Patel NM, Newton TR, King AJ, Marshall MS, Ali S, Nakshatri Het al., 2004, Tumour necrosis factor and PI3-kinase control oestrogen receptor alpha protein level and its transrepression function, BRITISH JOURNAL OF CANCER, Vol: 90, Pages: 853-859, ISSN: 0007-0920

Journal article

Vigushin DM, Dong Y, Inman L, Peyvandi N, Alao JP, Sun C, Ali S, Niesor EJ, Bentzen CL, Coombes RCet al., 2004, The nuclear oxysterol receptor LXR alpha is expressed in the normal human breast and in breast cancer, MEDICAL ONCOLOGY, Vol: 21, Pages: 123-131, ISSN: 1357-0560

Journal article

Shou J, Massarweh S, Osborne C K, Wakeling A E, Ali S, Weiss H, Schiff Ret al., 2004, Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer, J Natl Cancer Inst, Vol: 96, Pages: 926-935

Journal article

ALI SIMAK, GARCIA-LOPEZ JORGE, THOMAS ROSS, 2004, ER Inhibitor Peptide

Patent

Buluwela L, Constantinidou D, Pike J, Ali Set al., 2004, Estrogen receptors and anti-estrogen therapies., Cancer Treat Res, Vol: 119, Pages: 271-292, ISSN: 0927-3042

Journal article

SN Lauber, S Ali, NJ Gooderham, 2004, The cooked food derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine is a potent oestrogen: a mechanistic basis for its tissue-specific carcinogenicity., Carcinogenesis, Vol: 25, Pages: 2509-2517

Journal article

Singh A, Ali S, Kothari MS, De Bella MT, Smith C, Timms E, Slade MJ, Foxwell BM, Coombes RCet al., 2003, Reporter gene assay demonstrates functional differences in estrogen receptor activity in purified breast cancer cells: A pilot study, INTERNATIONAL JOURNAL OF CANCER, Vol: 107, Pages: 700-706, ISSN: 0020-7136

Journal article

ALI SIMAK, 2003, METHODS TO MODULATE THE ACTIVITY OF THE OESTROGEN RECEPTOR

Journal article

ALI Simak, 2003, METHODS TO MODULATE THE ACTIVITY OF THE OESTROGEN RECEPTOR

A polypeptide having the amino acid sequence of Seq ID No 1; Figure 1A or an amino acid sequence having at least 45 or 50 % identity with the amino acid sequence of Seq ID No 1 for use in medicine. Use of a compound for modulating, for example a nuclear receptor DNA binding protein, wherein the compound is: (a) the polypeptide ERZFP (SEQ ID No 1; Figure 1A); or, (b) a fragment of the polypeptide ERZPF which binds to the transcription factor, for example a nuclear receptor DNA binding protein; or, (c) a variant of the polypeptide or fragment as defined in (a) or (b) which binds to the transcription factor, for example a nuclear receptor DNA binding protein; or (d) a fusion or derivative of the polypeptide or fragment as defined in (a), (b) or (c) which binds to the transcription factor, for example a nuclear receptor DNA binding protein; or (e) a peptidomimetic of the polypeptide, fragment, variant, fusion or derivative as defined in (a), (b), (c), or (d) which binds to the transcription factor, for example a nuclear receptor DNA binding protein; or, (f) a compound, for example an antibody or antibody fragment which mimics the binding of the polypeptide, fragment, variant, fusion or derivative as defined in (a), (b), (c), or (d) to the transcription factor, for example a nuclear receptor DNA binding protein. A method for identifying a compound which modulates, for example promotes the transcription factor activity of a transcription factor, for example a nuclear receptor DNA binding protein, comprising the steps of: (a) providing the transcription factor, for example a nuclear receptor DNA binding protein or a fragment thereof comprising the AF1 domain for fragment thereof, and a compound as defined above; (b) exposing a test compound to the transcription factor, for example a nuclear receptor DNA binding protein or fragment and/or a compound as defined above; (c) determining whether the test compound modulates, for example inhibits, the ability of the transcription

Journal article

Chen DS, Lucey MJ, Phoenix F, Lopez-Garcia J, Hart SM, Losson R, Buluwela L, Coombes RC, Chambon P, Schar P, Ali Set al., 2003, T : G mismatch-specific thymine-DNA glycosylase potentiates transcription of estrogen-regulated genes through direct interaction with estrogen receptor alpha, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 278, Pages: 38586-38592, ISSN: 0021-9258

Journal article

Martin LA, Farmer I, Johnston SRD, Ali S, Marshall C, Dowsett Met al., 2003, Enhanced estrogen receptor (ER) alpha, ERBB2, and MAPK signal transduction pathways operate during the adaptation of MCF-7 cells to long term estrogen deprivation, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 278, Pages: 30458-30468, ISSN: 0021-9258

Journal article

Kothari MS, Ali S, Buluwela L, Livni N, Shousha S, Sinnett HD, Vashisht R, Thorpe P, Van Noorden S, Coombes RC, Slade MJet al., 2003, Purified malignant mammary epithelial cells maintain hormone responsiveness in culture, British Journal of Cancer, Vol: 88, Pages: 1071-1076, ISSN: 1532-1827

Currently, the therapy for breast cancer is determined by immunohistochemical staining of the primary tumour for oestrogen receptor alpha (ERα). However, a proportion of ERα-positive patients fail to respond to tamoxifen and a proportion of ERα-negative patients show response. Here, we describe a novel procedure for the purification of malignant breast epithelial cells in an attempt to identify these patients at an early stage. Using this procedure, we are able to purify malignant cells to >90% purity as determined by immunohistochemical staining, cytology and fluorescent in situ hybridisation (FISH). While the malignant cells can be maintained in culture they do not proliferate in contrast to purified breast epithelial cells from reduction mammoplasties. Moreover, ERα and progesterone receptor (PR) expression is maintained in malignant cells, whereas normal epithelial cells rapidly lose ERα and PR. Functional studies were performed on the separated malignant cells in terms of their response to oestradiol and tamoxifen. Four out of the seven ERα-positive tumours showed a significant reduction in cell numbers after tamoxifen treatment compared to oestradiol, ERα negative tumours failed to show a response. We conclude that (a) it is possible to purify and maintain breast cancer cells for a sufficient period to permit functional studies and (b) ERα is retained in culture facilitating the use of these cells in studies of the mechanism of endocrine response and resistance in vitro.

Journal article

Simak Ali, Laki Buluwela, David Holmes, Tahereh Kamalati, Jonathan Waxmanet al., 2003, Silencing of endogenous gene expression, WO03010308

Patent

VAINIKKA SATU, HART STEPHEN, ALI SIMAK, PUFONG BORIS TUMI, PORTER ANDREW CHRISTOPHER GEOR, BULUWELA LAKI, JENKINSON JOHN DAVID, KANDA PATRICKet al., 2002,

Journal article

HART STEPHEN, ALI SIMAK, PUFONG BORIS, PORTER ANDREW CHRISTOPHER GEOR, BULUWELA LAKI, VAINIKKA SATUet al., 2002,

Journal article

HART STEPHEN, ALI SIMAK, PUFONG BORIS TUMI, PORTER ANDREW CHRISTOPHER, BULUWELA LAKI, VAINIKKA SATU, JENKINSON JOHN DAVID, KANDA PATRICKet al., 2002,

Journal article

HART STEPHEN, ALI SIMAK, PUFONG BORIS TUMI, PORTER ANDREW CHRISTOPHER GEORGE, BULUWELA LAKI, VAINIKKA SATU, JENKINSON JOHN DAVID, KANDA PATRICKet al., 2002, CONTROL OF GENE EXPRESSION USING A COMPLEX OF AN OLIGONUCLEOTIDE AND A REGULATORY PEPTIDE

A method for suppressing the expression of a selected gene in a cell the method comprising introducing into the cell a molecule comprising (1) a nucleic acid binding portion which binds to a site or associated with the selected gene which site is present in a genome and (2) an expression repressor portion, wherein the nucleic acid binding portion comprises an oligonucleotide or oligonucleotide mimic or analogue, and wherein the repressor portion comprises a polypeptide or peptidomimetic. Molecules for use in the methods of the invention are provided. The repressor may be a portion of a histone deacetylase or DNA methylase or polypeptide capable of recruiting a histone deacetylase or DNA methylase.

Journal article

HART STEPHEN, ALI SIMAK, PUFONG BORIS, PORTER ANDREW, BULUWELA LAKI, VAINIKKA SATU, JENKINSON JOHN, KANDA PATRICKet al., 2002,

Journal article

Chan CMW, Martin LA, Johnston SRD, Ali S, Dowsett Met al., 2002, Molecular changes associated with the acquisition of oestrogen hypersensitivity in MCF-7 breast cancer cells on long-term oestrogen deprivation, JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, Vol: 81, Pages: 333-341, ISSN: 0960-0760

Journal article

Chen DS, Washbrook E, Sarwar N, Bates GJ, Pace PE, Thirunuvakkarasu V, Taylor J, Epstein RJ, Fuller-Pace FV, Egly JM, Coombes RC, Ali Set al., 2002, Phosphorylation of human estrogen receptor alpha at serine 118 by two distinct signal transduction pathways revealed by phosphorylation-specific antisera, ONCOGENE, Vol: 21, Pages: 4921-4931, ISSN: 0950-9232

Journal article

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