Molecular Oncology and New Therapeutic Targets

Our lab investigates the molecular and cellular mechanisms associated to breast and prostate cancer growth and progression. Our goal is to identify new biomarkers for early breast and prostate cancer diagnosis, prognosis and/or therapy.

Molecular Oncology and New Therapeutic Targets

  • Lab Director

    Ph.D. Adriana De Siervi Currículum Vitae

    Independent Investigator, CONICET

  • Lab Members

    Paola De Luca, Ph. D. (Assistant Researcher, CONICET) paoladeluca81@yahoo.com.ar

    Flavia Piccioni, Ph. D. (Postdoctoral Fellow CONICET) flapiccioni84@gmail.com

    Nicolás Dalton (Ph.D. Student ANPCyT) nico_dalton@hotmail.com

    Cintia Massillo (Ph.D. Student CONICET) cintiamassillo@gmail.com

    Juliana Porretti (Ph.D. Student CONICET) julianaporretti@gmail.com

    Georgina Scalise, M.D. (INC fellow) gescalise@yahoo.com

    Paula Lucia Farré (INC fellow) paulafarre@gmail.com

    Rocío Belén Duca (Undergraduate student-INC fellow) rochiducaa@gmail.com

    Karen Graña (Undergraduate student) karen.g@hotmail.com.ar

    Camila Zaslavsky (Undergraduate student) camilazaslavsky@hotmail.com

     

Research project

MeS is a cluster of pathophysiological disorders that comprises at least three of the following factors: abdominal obesity (waist circumference ≥ 35 inches in women), triglycerides ≥150 mg/dL, high density lipoprotein cholesterol (HDL-C), blood pressure ≥ 130/85 mmHg, and fasting glucose ≥ 110 mg/dL. Several studies have established that components of MeS are positively correlated with breast and prostate cancer risk.

Recently, we generated one MeS mice model by chronic administration of fat diet. This model allowed us to identify key genes that link MeS and prostate or breast cancer development and progression. Thus, we found C-terminal Binding Protein (CtBP1) that is a transcription co-repressor of tumor suppressor genes. Our findings determined that CtBP1 expression diminution in prostate or breast cancer cells injected into nude mice, dramatically decreased tumor growth.

Using mRNA and miRNA expression microarrays together with bioinformatic tools, we identified several genes regulated by CtBP1 that directly modulates cell adhesion impacting over metastasis development. Thus, we found CDH1, COL17A1, PRRS2, CDH3, ITGB4, TGM2, LCN2, GJB5 and CLCA2, among others. Therefore, we identified a cluster of miRNAs regulated by CtBP1 involved in tumor progression: miR-205; miR-29c; miR-335. miRNAs (microRNAs) can regulate several genes or cellular processes. Thus, miRNAs are interesting molecules that might be used as biomarkers for the diagnosis and/or therapy.

Based in these findings we are currently establishing collaboration with different clinical institutions to develop clinical trials to identify miRNAs for the early diagnosis of breast or prostate cancer in patients  

In summary, our research Project currently is divided into four areas:

  • CtBP1 rol in breast and prostate tumor growth and progression associated to MeS.
  • Identify new biomarkers for breast and prostate cancer early diagnosis based in miRNAs.
  • Identify new biomarkers for breast cancer therapy based in miRNAs.
  • Establish epigenetic alterations associated to breast and prostate cancer tumor growth.

Ph.D. Thesis

Paola De Luca. Mentor: Adriana De Siervi. Departamento de Química Biológica, FCEyN – UBA, from 4/1/07. Defended 12/29/11. Reviewers: Dr. Mónica Costas, Dr. Eduardo Cánepa, Dr. Omar Coso. Title: “BRCA1 role in the regulation of transcription in prostate cancer”.  Oustanding.

Cristian Moiola. Mentor: Adriana De Siervi. Departamento de Química Biológica, FCEyN – UBA, from 7/1/08. Defended 3/8/2013.  “New molecular targets in the prostate cancer”. Reviewers: Dr. Mónica Vazquez-Levin, Dr. Marina Simian, Dr. Adalí Pecci. Oustanding.

Belén Elguero. Mentor: Elba Vazquez. Assistant director: Adriana De Siervi. Departamento de Química Biológica, FCEyN – UBA, from 10/1/08. Defended 5/28/2013. “HO-1 role in the regulation of the inflammation associated to prostate cancer”. Oustanding.

Florencia Zalazar. Mentor: Adriana De Siervi. Departamento de Química Biológica, FCEyN – UBA, from 1/4/09. Defended 5/11/2015. “New therapeutic strategies for androgen independent prostate cancer”. Reviewers: Dr. Mónica Costas, Dr. Marina Simian, Dr. Alejandro Curino. Oustanding.

Nicolás Dalton. Mentor: Adriana De Siervi. Laboratory of Molecular Oncology and New Therapeutic Targets (IBYME – CONICET), from 5/1/14. “Molecular studies that associates metabolic síndrome and prostate cancer”. Ongoing.

Cintia Massillo. Mentor: Adriana De Siervi. Laboratory of Molecular Oncology and New Therapeutic Targets (IBYME – CONICET), from 6/1/14.  “Epigenetic alterations associated to high fat diet and prostate cancer development.” Ongoing.

Juliana Porretti. Mentor: Adriana De Siervi. Laboratory of Molecular Oncology and New Therapeutic Targets (IBYME – CONICET), from 6/1/14.  “New molecular tools for early diagnosis and cancer therapy in a metabolic syndrome animal model.” Ongoing.

Publications (last 13 years)
  1. Massillo CL, Dalton GN, Farré PL, De Luca P & De Siervi A. Implications of microRNA dysregulation in the development of prostate cancer. Reproduction. 2017. In press.
  2. Leonardi DB, Abbate M, Riccheri MC, Nuñez M, Alfonso G, Gueron G, De Siervi A, Vazquez E, Cotignola J. Improving risk stratification of patients with childhood acute lymphoblastic leukemia: Glutathione-S-Transferases polymorphisms are associated with increased risk of relapse. Oncotarget. 2017. 8(1):110-117. doi: 10.18632/oncotarget.8606.
    https://www.ncbi.nlm.nih.gov/pubmed/27058755
  3. De Luca P, Dalton GN, Scalise GD, Moiola CP, Porretti J, Massillo C, Kordon E, Gardner K, Zalazar F, Flumian C, Todaro L, Vazquez ES, Meiss R, De Siervi A. CtBP1 associates metabolic syndrome and breast carcinogenesis targeting multiple miRNAs. Oncotarget. 2016. 7(14):18798-811.
    https://www.ncbi.nlm.nih.gov/pubmed/26933806
  4. De Luca P, De Siervi A. Critical role for BRCA1 expression as a marker of chemosensitivity response and prognosis. Frontiers in Bioscience.2016. 8:72-83.
    https://www.ncbi.nlm.nih.gov/pubmed/26709647
  5. Labanca E, De Luca P, Gueron G, Paez A, Moiola CP, Massillo C, Porretti J, Giudice J, Zalazar F, Navone N, Vazquez E, De Siervi A. Association of HO-1 and BRCA1 is Critical for the Maintenance of Cellular Homeostasis in Prostate Cancer. Mol Cancer Res. 2015. 13(11):1455-64.
    Highlighted in the issue. https://www.ncbi.nlm.nih.gov/pubmed/26227317
  6. Zalazar F, De Luca P, Gardner K, Figg WD, Meiss R; Spallanzani RG; Vallecorsa P; Elguero B; Cotignola J; Vazquez E & De Siervi A. Low doses of CPS49 and flavopiridol combination as potential treatment for advanced prostate cancer. Curr Pharm Biotechnol. 16(6):553-63. (2015)
    https://www.ncbi.nlm.nih.gov/pubmed/25860066
  7. Moiola CP, De Luca P, Zalazar F, Cotignola J, Rodriguez-Segui S, Gardner K, Meiss R, Vallecorsa P, Pignataro O, Mazza O, Vazquez ES, De Siervi A. Prostate tumor growth is impaired by CtBP1 depletion in high fat diet fed mice. Clinical Cancer Research. 20(15):4086-95. (2014)
    https://www.ncbi.nlm.nih.gov/pubmed/24842953
  8. Ferrando M, Wan X, Meiss R, Yang J, De Siervi A, Navone N, Vazquez E. Heme Oxygenase-1 (HO-1) Expression in Prostate Cancer Cells Modulates the Oxidative Response in Bone Cells. PLoS One. 2013;8(11):e80315.
    https://www.ncbi.nlm.nih.gov/pubmed/24224047
  9. De Luca P, Moiola C, Zalazar F, Gardner K, Vazquez E & De Siervi A. BRCA1 and p53 regulate critical prostate cancer pathways. Prostate Cancer and Prostatic Diseases.16(3):233-8. (2013)https://www.ncbi.nlm.nih.gov/pubmed/23670255
  10. Palm T, Hemmer K, Winter J, Fricke I, Tarbashevich K, Sadeghi Shakib F, Rudolph IM, Hillje AL, De Luca P, Bahnassawy L, Madel R, Viel T, De Siervi A, Jacobs A, Diederichs S, Schwamborn J. A systemic transcriptome analysis reveals the regulation of neural stem cell maintenance by an E2F1-miRNA feedback loop. Nucleic Acids Research.41(6):3699-3712 (2013).
    https://www.ncbi.nlm.nih.gov/pubmed/23396440
  11. Cotignola J, Leonardi D, Shahabi A, Acuña A, Stern M, Navone N, Scorticati C, De Siervi A, Mazza O & Vazquez E. Glutathione-S-Transferase (GST) polymorphisms are associated with relapse after radical prostatectomy. Prostate Cancer & Prostatic Diseases. 16(1):28-34. (2013).
    https://www.ncbi.nlm.nih.gov/pubmed/23146971
  12. Elguero B, Gueron G, Giudice J, Toscani M, De Luca P, Zalazar F, Coluccio-Leskow F, Meiss R, Navone N, De Siervi A & Vazquez E. Unveiling the Association of STAT3 and HO-1 in Prostate Cancer: Role beyond Heme Degradation. Neoplasia. 14(11):1043-56. (2012).
    https://www.ncbi.nlm.nih.gov/pubmed/23226098
  13. Moiola C, De Luca P, Cotignola J, Gardner K, Vazquez E & De Siervi A. Dynamic coregulatory complex containing BRCA1, E2F1 and CtIP controls ATM transcription. Cellular Physiology and Biochemistry. 30(3):596-608. (2012).
    https://www.ncbi.nlm.nih.gov/pubmed/22832221
  14. Gueron G, De Siervi A, Vazquez E. Advanced prostate cancer: reinforcing the strings between inflammation and the metastatic behavior. Prostate Cancer & Prostatic Diseases.15(3):213-21 (2012).
    https://www.ncbi.nlm.nih.gov/pubmed/22183772
  15. Ferrando M, Gueron G, Elguero B, Giudice J, Salles A, Leskow FC, Jares-Erijman EA, Colombo L, Meiss R, Navone N, De Siervi A, Vazquez E. Heme oxygenase 1 (HO-1) challenges the angiogenic switch in prostate cancer. Angiogenesis. 14(4):467-479 (2011). https://www.ncbi.nlm.nih.gov/pubmed/21833623
  16. De Luca P, Vazquez E, Moiola C, Zalazar F, Cotignola J, Gueron G, Gardner K & De Siervi A. BRCA1 loss induces GADD153-mediated doxorubicin resistance in prostate cancer. Mol. Cancer Res. 9(8):1078-90 (2011).
    https://www.ncbi.nlm.nih.gov/pubmed/21700680
  17. Gueron G, De Siervi A & Vazquez E. Key Questions in Metastasis: New Insights in Molecular Pathways and Therapeutic Implications. Curr Pharm Biotechnol. 12: 1867- 80 (2011).
    https://www.ncbi.nlm.nih.gov/pubmed/21470130
  18. Di LJ, Fernandez AG, De Siervi A, Longo D & Gardner K. Transcriptional regulation of BRCA1 expression by a metabolic switch. Nat. Struct. & Mol. Biol. 17: 1406–1413 (2010).
    http://www.cancer.gov/newscenter/pressreleases/BRCA1proteinobesity
    Highlighted as the best article of the month in the issue: http://www.nature.com/nsmb/journal/v17/n12/index.html#rhighlts
    https://www.ncbi.nlm.nih.gov/pubmed/21102443
  19. Moiola C, De Luca P, Gardner K, Vazquez E & De Siervi A. Cyclin T1 overexpression induces malignant transformation and tumor growth. Cell cycle.9(15):3119-26 (2010).
    https://www.ncbi.nlm.nih.gov/pubmed/20714219
  20. De Siervi A, De Luca P, Byun JS, Di LJ, Fufa T, Haggerty CM, Vazquez E, Moiola C, Longo DL, Gardner K. Transcriptional autoregulation by BRCA1. Cancer Res. 70(2):532-42 (2010).
    https://www.ncbi.nlm.nih.gov/pubmed/20068145
  21. Gueron G, De Siervi A, Ferrando M, Salierno M, De Luca P, Elguero B, Meiss R, Navone N, Vazquez ES. Critical role of endogenous heme oxygenase 1 as a tuner of the invasive potential of prostate cancer cells. Mol Cancer Res. 7(11):1745-55 (2009). https://www.ncbi.nlm.nih.gov/pubmed/19903769
  22. Byun JS, Wong MM, Cui W, Idelman G, Li Q, De Siervi A, Bilke S, Haggerty CM, Player A, Wang YH, Thirman MJ, Kaberlein JJ, Petrovas C, Koup RA, Longo D, Ozato K, Gardner K. Dynamic bookmarking of primary response genes by p300 and RNA polymerase II complexes. Proc Natl Acad Sci USA. 106(46):19286-91 (2009).
    https://www.ncbi.nlm.nih.gov/pubmed/19880750
  23. De Siervi A, De Luca P, Moiola C, Gueron G, Tongbai R, Chandramouli GV, Haggerty C, Dzekunova I, Petersen D, Kawasaki E, Kil WJ, Camphausen K, Longo D, Gardner K. Identification of new Rel/NFkappaB regulatory networks by focused genome location analysis. Cell Cycle.8(13):2093-100 (2009).
    https://www.ncbi.nlm.nih.gov/pubmed/19502793
  24. Macias E, Miliani de Marval PL, De Siervi A, Conti CJ, Senderowicz AM, Rodriguez-Puebla ML. CDK2 activation in mouse epidermis induces keratinocyte proliferation but does not affect skin tumor development. Am J Pathol.173(2):526-35 (2008).
    https://www.ncbi.nlm.nih.gov/pubmed/18599613
  25. Ge Y, Byun JS, De Luca P, Gueron G, Li QQ, Yabe IM, Sadiq-Ali SG, Figg WD, Quintero J, Haggerty CM, De Siervi A, Gardner K. Combinatorial anti-leukemic disruption of oxidative homeostasis and mitochondrial stability by the redox reactive thalidomide CPS49 and flavopiridol. Mol Pharmacol. 74(3):872-83 (2008).
    https://www.ncbi.nlm.nih.gov/pubmed/18556456
  26. Smith J, Freebern WJ, Collins I, De Siervi A, Montano I, Haggerty CM, McNutt MC, Butscher WG, Dzekunova I, Petersen DW, Kawasaki E, Merchant JL, Gardner K. Kinetic profiles of p300 occupancy in vivo predict common features of promoter structure and coactivator recruitment. Proc Natl Acad Sci USA.101(32):11554-11559 (2004).
    https://www.ncbi.nlm.nih.gov/pubmed/15286281
  27. De Siervi A, Marinissen MJ, Diggs J, Wang X-F, Pages Gilles & Senderowicz AM Transcriptional activation of p21waf1/cip1 by alkylphospholipids. Role of the MAPK pathway in the transactivation of the human p21waf1/cip1 promoter by Sp1. Cancer Res 64:743-750 (2004).
    https://www.ncbi.nlm.nih.gov/pubmed/14744793
  28. Facchinetti MM, De Siervi A, Toskos D & Senderowicz AM UCN-01-induced cell cycle arrest requires the transcriptional induction of p21(waf1/cip1) by activation of mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase pathway. Cancer Res. 64(10):3629-3637 (2004)
    https://www.ncbi.nlm.nih.gov/pubmed/15150122
Awards

2012. Award: ATM transcriptional regulation mediated by BRCA1/E2F1 axis controls DNA damage response in prostate cancer. Authors: Moiola C, De Luca P, Zalazar F, Cotignola J, Gardner K, Vazquez E, De Siervi A. Selected abstract from the top 5% best posters presented at 103rd Annual Meeting American Association for Cancer Research AACR (Chicago, USA, March 31st to April 4th 2012). Proc. AACR (2012) 53: p.270. Abstract: 1312 (poster).

2013. MONTOURI-FUNDACION GADOR Oncology Award: “CtBP1 es un sensor metabólico molecular que media el desarrollo tumoral prostático dependiente de una dieta rica en grasas.” Authors: Moiola C, De Luca P, Zalazar F, Cotignola J, Meiss R, Vallecorsa P, Mazza O, Scorticati C, Paz D, Pignataro O, Vazquez E, De Siervi A. LVIII Reunión Científica Anual de la SAIC (Mar del Plata, Buenos Aires, Argentina) November 20 – 23, 2013). Medicina. Amount U$2.000.

Grants

PICT 2015 (1345) Plan Argentina Innovadora 2020: Molecular studies that associates metabolic syndrome and breast and prostate cancer growth. Amount: U$60,000. Ongoing. PI: Adriana De Siervi; Co-PI: Paola De Luca.

PICT 2014 (324) Plan Argentina Innovadora 2020: MicroRNAs: new molecular tolos for cancer early diagnosis and therapy in a metabolic syndrome animal model. Amount: U$40,000. Ongoing. PI: Adriana De Siervi.

PICT 2013 (2151) CtBP1 role in the malignat transformation process and the molecular mechanisms that associate high fat diet and breast tumor development. Amount: U$8,000. Expired.PI: Paola De Luca.

PICT 2012 (374). PI: Adriana De Siervi. Molecular studies that associate hipercaloric diet and breast and prostate cancers. Amount: U$33,000. Expired.

Financial assistance to cancer projects from National Cancer Institute (Argentina) 2012-2014: Molecular studies that associate obesity and breast and prostate cancer risks. PI: Adriana De Siervi. Amount: U$40,000. Expired.  

PICT RAICES 2010-2013 (431), PI Elba Vazquez. Co-PI: Adriana De Siervi.Nuclear localization of Heme Oxygenase 1 (HO1) in prostate cancer: a function beyond heme degradation.  Amount: U$90,000. Expired.

PICT 2006-2009 (228), PI: Adriana De Siervi. BRCA1 role in prostate cancer. Amount: U$90,000. Expired.

PICT RAICES 2006-2009 (367), PI Elba Vazquez. Co-PI: Adriana De Siervi.HO1 and VEGF role in bone metastasis from prostate cancer.  Amount: U$90,000. Expired.

Undergraduate Thesis

Marina Ruiz Grecco. Mentor: Adriana De Siervi. Assistant director: Elba Vazquez. “Transcriptional regulation of BRCA1 in prostate cancer” Department of Biological Chemistry, FCEyN – UBA, defended 3/14/08.

Mercedes Ferrando. Mentor: Elba Vazquez. Assistant director: Adriana De Siervi. “Studies about HO-1 and VEGF expression in prostate cancer” Department of Biological Chemistry, FCEyN – UBA, defended 3/20/08.

Julián Chamorro. Mentor: Adriana De Siervi. Assistant director: Elba Vazquez. “Transcriptional regulation of GADD153 in prostate cancer” Department of Biological Chemistry, FCEyN – UBA, defended 11/08.

Florencia Zalazar. Mentor: Adriana De Siervi. Assistant director: Elba Vazquez. “Transcriptional regulation of Prostatic Specific Antigen (PSA)” Department of Biological Chemistry, FCEyN – UBA, defended 3/18/09.

Federico Aranda. Mentor: Elba Vazquez. Assistant director: Adriana De Siervi.  “IL-8 effect over HO-1 expression in prostate cancer cell lines” Department of Biological Chemistry, FCEyN – UBA, defended 4/14/09.

Nicolás Dalton. Mentor: Adriana De Siervi. Assistant director: Paola De Luca. “Hipercaloric diet effects over CtBP1/BRCA1 pathway in breast tumor cell lines.” Department of Biological Chemistry, FCEyN – UBA, defended 12/19/2013.

Estefanía Labanca. Mentor: Adriana De Siervi. Assistant director: Paola De Luca. “Cellular homeostasis mediated by BRCA1 and HO-1.” Department of Biological Chemistry, FCEyN – UBA, IBYME – CONICET. Defended 4/11/2014.

Paula Lucía Farré. Mentor: Paola De Luca. “Rol of CtBP1 in the breast cancer metástasis in the metabolic síndrome context”. FCEN – UBA, IBYME – CONICET, defended 12/04/2016.

Collaborations

Dr. Kevin Gardner

Acting Scientific Director

National Institute on Minority Health and Health Disparities (NIMHD)

National Cancer Institute (NCI)

National Institutes of Health (NIH), USA

He is specialist in transcription and cancer studies. His group has a wide experience in the use of bioinformatic tools and microarray analysis. 

 

Dr. Roberto Meiss

Pathologist Chief

Academia Nacional de Medicina, Buenos Aires

He is a renamed pathologist that collaborate with our group in the discussion of results. He clarifies and provides ideas related to metabolism, MeS and obesity.

 

Dr. Norma Alejandra Chasseing

Principal Investigator CONICET

Director of the Laboratory of immunohematology (IBYME)

She is specialist in the study of the role of estromal microenvironment in the evolution of cancer.

 

Dr. Karina Mariño

Independent Investigator CONICET

Director of the Laboratory of Functional and Molecular Glycomic (IBYME)

She is specialist in the glycomic studies.

 

Dr. Débora Cohen and Dr. Vanina Da Ros

Researchers from CONICET

Laboratory of Molecular Mechanisms of the Fertilization (IBYME)

She is specialist in fertilization field.

 

Dr. Norberto W. Zwirner

Principal Investigator CONICET

Director of the Laboratory of the Physiopathology and Immunity Innate

He is specialist in immunology.,

 

 

CLINICAL TRIALS

 

Dr. Nicolás García

Urologist

Hospital Militar Central

Ciudad de Buenos Aires

Director of the protocol entitled: “Circulating MicroRNAs: new molecular tools for prostate cancer early diagnosis.”

 

Dr. María Marta Facchinetti

Independent Investigator CONICET

She established the clinical protocol in the Hospital Municipal (Bahía Blanca) entitled: “Circulating MicroRNAs: new molecular tools for prostate cancer early diagnosis.”

 

Dr. Mónica Casalnuovo

Oncologist

Hospital Municipal de Oncología Marie Curie

Ciudad de Buenos Aires

Director of the protocol entitled: “Circulating MicroRNAs: new molecular tools for breast cancer early diagnosis.”

 

Dr. Emilio Batagelj

Oncologist

Hospital Militar Central

Ciudad de Buenos Aires

Director of the protocol entitled: “Circulating MicroRNAs: new molecular tools for breast cancer early diagnosis.”

 

Dr. Federico Dimase

Hematologist

Hospital Militar Central

Ciudad de Buenos Aires

Director of the protocol entitled: “Circulating MicroRNAs: new molecular tools for breast cancer early diagnosis.” (healthy donors)

 

Dr. Marcelo Pannunzio, Dr. Luis Pepa, Dra. Nora Falcoff

Ginecologists and pathologist

Hospital Municipal Dr. Bernardo Houssay

Vicente López, Buenos Aires

Director of the protocol entitled: “Circulating MicroRNAs: new molecular tools for breast cancer early diagnosis.”

Laboratories
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