Photo of Gerburg Wulf,  MD, PhD

Gerburg Wulf, MD, PhD

Beth Israel Deaconess Medical Center

Beth Israel Deaconess Medical Center
Phone: (617) 667-1910
Fax: (617) 667-0610


gwulf@bidmc.harvard.edu

Gerburg Wulf, MD, PhD

Beth Israel Deaconess Medical Center

EDUCATIONAL TITLES

  • Associate Professor, Medicine, Harvard Medical School
  • Active Staff, Hematology/Oncology, Beth Israel Deaconess Medical Center

DF/HCC PROGRAM AFFILIATION

Research Abstract

Much cancer research focuses on the molecular mechanisms of neoplastic transformation with the hope that understanding the mechanisms of carcinogenesis will provide keys to the development of new therapeutic avenues. A major therapeutic target is the cell cycle machinery of cancer cells. My work in the last several years has focused on the mechanisms that link cell cycle control with oncogenesis, specifically on the role of the prolyl isomerase Pin1 in breast cancer.

Pin1 regulates the function of a subset of phosphoproteins, presumably by binding and isomerizing their phosphorylated S/T-P motifs. Inhibition of Pin1 causes growth arrest in tumor cells and contributes to neuronal death in Alzheimer's disease. We found that Pin1 is overexpressed in human breast cancer cell lines and 75% of breast cancer tissues, and that its levels correlate with the nuclear grade of the tumors and their cyclin D1 protein and mRNA expression. Pin1 mRNA levels were elevated in those tumors examined suggesting that Pin1 expression is at least in part regulated on the transcriptional level. Induced expression of Pin1 elevates cellular cyclin D1 levels and activates its promoter through the AP-1 site. Importantly, Pin1 binds to phosphorylated c-Jun and dramatically increases its ability to activate the cyclin D1 promoter in cooperation either with oncogenic Ha-Ras or activated JNK; these effects depend on phosphorylation of c-Jun on S63/73-P and the isomerase activity of Pin1. Given the crucial roles of Ras signaling and cyclin D1 overexpression in oncogenesis, my results suggest that overexpression of Pin1 may promote tumor growth. To examine this hypothesis, I am currently analyzing the significance of Pin1 for mammary tumorigenesis in a mouse model.

Publications

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  • Liu H, Paddock MN, Wang H, Murphy CJ, Geck RC, Navarro AJ, Wulf GM, Elemento O, Haucke V, Cantley LC, Toker A. The INPP4B Tumor Suppressor Modulates EGFR Trafficking and Promotes Triple Negative Breast Cancer. 2020. PubMed
  • Li Q, Qin T, Bi Z, Hong H, Ding L, Chen J, Wu W, Lin X, Fu W, Zheng F, Yao Y, Luo ML, Saw PE, Wulf GM, Xu X, Song E, Yao H, Hu H. Rac1 activates non-oxidative pentose phosphate pathway to induce chemoresistance of breast cancer. Nat Commun 2020; 11:1456. PubMed
  • Luo ML, Zheng F, Chen W, Liang ZM, Chandramouly G, Tan J, Willis NA, Chen CH, de Oliveira Taveira M, Zhou XZ, Lu KP, Scully R, Wulf GM, Hu H. Inactivation of the prolyl isomerase Pin1 sensitizes BRCA1-proficient breast cancer to PARP inhibition. Cancer Res 2020. PubMed
  • Przybytkowski E, Davis T, Hosny A, Eismann J, Matulonis UA, Wulf GM, Nabavi S. An immune-centric exploration of BRCA1 and BRCA2 germline mutation related breast and ovarian cancers. BMC Cancer 2020; 20:197. PubMed
  • Becker S, Kiecke C, Schaefer E, Sinzig U, Deuper L, Trigo-Mourino P, Griesinger C, Koch R, Rydzynska Z, Chapuy B, von Bonin F, Kube D, Venkataramani V, Bohnenberger H, Leha A, Flach J, Dierks S, Bastians H, Maruschak B, Bojarczuk K, de Oliveira Taveira M, Trumper L, Wulf GM, Wulf GG. Destruction of a microtubule-bound MYC reservoir during mitosis contributes to vincristines anti-cancer activity. Mol Cancer Res 2020. PubMed
  • Eismann J, Heng YJ, Waldschmidt JM, Vlachos IS, Gray KP, Matulonis UA, Konstantinopoulos PA, Murphy CJ, Nabavi S, Wulf GM. Transcriptome analysis reveals overlap in fusion genes in a phase I clinical cohort of TNBC and HGSOC patients treated with buparlisib and olaparib. J Cancer Res Clin Oncol 2019. PubMed
  • Gómez-Miragaya J, Díaz-Navarro A, Tonda R, Beltran S, Palomero L, Palafox M, Dobrolecki LE, Huang C, Vasaikar S, Zhang B, Wulf GM, Collado-Solé A, Trinidad EM, Muñoz P, Paré L, Prat A, Bruna A, Caldas C, Arribas J, Soler-Monsó MT, Petit A, Balmaña J, Cruz C, Serra V, Pujana MA, Lewis MT, Puente XS, González-Suárez E. Chromosome 12p amplification in triple-negative/BRCA1-mutated breast cancer associates with emergence of docetaxel resistance and carboplatin sensitivity. Cancer Res 2019. PubMed
  • Vinayak S, Tolaney SM, Schwartzberg L, Mita M, McCann G, Tan AR, Wahner-Hendrickson AE, Forero A, Anders C, Wulf GM, Dillon P, Lynce F, Zarwan C, Erban JK, Zhou Y, Buerstatte N, Graham JR, Arora S, Dezube BJ, Telli ML. Open-Label Clinical Trial of Niraparib Combined With Pembrolizumab for Treatment of Advanced or Metastatic Triple-Negative Breast Cancer. JAMA Oncol 2019. PubMed
  • Pantelidou C, Sonzogni O, De Oliveria Taveira M, Mehta AK, Kothari A, Wang D, Visal T, Li MK, Pinto J, Castrillon JA, Cheney EM, Bouwman P, Jonkers J, Rottenberg S, Guerriero JL, Wulf GM, Shapiro GI. PARP Inhibitor Efficacy Depends on CD8 T-cell Recruitment via Intratumoral STING Pathway Activation in BRCA-Deficient Models of Triple-Negative Breast Cancer. 2019; 9:722-737. PubMed
  • Konstantinopoulos PA, Barry WT, Birrer M, Westin SN, Cadoo KA, Shapiro GI, Mayer EL, O'Cearbhaill RE, Coleman RL, Kochupurakkal B, Whalen C, Curtis J, Farooq S, Luo W, Eismann J, Buss MK, Aghajanian C, Mills GB, Palakurthi S, Kirschmeier P, Liu J, Cantley LC, Kaufmann SH, Swisher EM, D'Andrea AD, Winer E, Wulf GM, Matulonis UA. Olaparib and α-specific PI3K inhibitor alpelisib for patients with epithelial ovarian cancer: a dose-escalation and dose-expansion phase 1b trial. Lancet Oncol. 2019; 20:570-580. PubMed
  • Sonzogni O, Millard AL, Taveira A, Schneider MKJ, Duo L, Speck RF, Wulf GM, Mueller NJ. Efficient Human Cytomegalovirus Replication in Primary Endothelial Cells Is SOCS3 Dependent. Intervirology 2019; 62:80-89. PubMed
  • Baker GM, Pyle ME, Tobias AM, Bartlett RA, Phillips J, Fein-Zachary VJ, Wulf GM, Heng YJ. Establishing a Cohort of Transgender Men and Gender Nonconforming Individuals to Understand the Molecular Impact of Testosterone on Breast Physiology. Transgend Health 2019; 4:326-330. PubMed
  • Xing Y, Lin NU, Maurer MA, Chen H, Mahvash A, Sahin A, Akcakanat A, Li Y, Abramson V, Litton J, Chavez-MacGregor M, Valero V, Piha-Paul SA, Hong D, Do KA, Tarco E, Riall D, Eterovic AK, Wulf GM, Cantley LC, Mills GB, Doyle LA, Winer E, Hortobagyi GN, Gonzalez-Angulo AM, Meric-Bernstam F. Phase II trial of AKT inhibitor MK-2206 in patients with advanced breast cancer who have tumors with PIK3CA or AKT mutations, and/or PTEN loss/PTEN mutation. Breast Cancer Res 2019; 21:78. PubMed
  • Eismann J, Heng YJ, Fleischmann-Rose K, Tobias AM, Phillips J, Wulf GM, Kansal KJ. Interdisciplinary Management of Transgender Individuals at Risk for Breast Cancer: Case Reports and Review of the Literature. Clin Breast Cancer 2018. PubMed
  • Al Moustafa AE, Ahmed HG, Wulf G, Sultan AA. Editorial: EBV-Associated Carcinomas: Presence, Role, and Prevention Strategies. 2018; 8:528. PubMed
  • Liu H, Murphy CJ, Karreth FA, Emdal KB, White FM, Elemento O, Toker A, Wulf GM, Cantley LC. Identifying and Targeting Sporadic Oncogenic Genetic Aberrations in Mouse Models of Triple Negative Breast Cancer. 2018. PubMed
  • Breitkopf SB, Taveira MO, Yuan M, Wulf GM, Asara JM. Serial-omics of P53-/-, Brca1-/- Mouse Breast Tumor and Normal Mammary Gland. Sci Rep 2017; 7:14503. PubMed
  • Liu JF, Palakurthi S, Zeng Q, Zhou S, Ivanova E, Huang W, Zervantonakis IK, Selfors LM, Shen Y, Pritchard CC, Zheng M, Adleff V, Papp E, Piao H, Novak M, Fotheringham S, Wulf GM, English J, Kirschmeier PT, Velculescu VE, Paweletz C, Mills GB, Livingston DM, Brugge JS, Matulonis UA, Drapkin R. Establishment of Patient-Derived Tumor Xenograft Models of Epithelial Ovarian Cancer for Preclinical Evaluation of Novel Therapeutics. Clin Cancer Res 2016. PubMed
  • de Oliveira Taveira M, Nabavi S, Wang Y, Tonellato P, Esteva FJ, Cantley LC, Wulf GM. Genomic characteristics of trastuzumab-resistant Her2-positive metastatic breast cancer. J Cancer Res Clin Oncol 2017. PubMed
  • Juvekar A, Hu H, Yadegarynia S, Lyssiotis CA, Ullas S, Lien EC, Bellinger G, Son J, Hok RC, Seth P, Daly MB, Kim B, Scully R, Asara JM, Cantley LC, Wulf GM. Phosphoinositide 3-kinase inhibitors induce DNA damage through nucleoside depletion. Proc Natl Acad Sci U S A 2016; 113:E4338-47. PubMed
  • Shim H, Wu C, Ramsamooj S, Bosch KN, Chen Z, Emerling BM, Yun J, Liu H, Choo-Wing R, Yang Z, Wulf GM, Kuchroo VK, Cantley LC. Deletion of the gene Pip4k2c, a novel phosphatidylinositol kinase, results in hyperactivation of the immune system. Proc Natl Acad Sci U S A 2016; 113:7596-601. PubMed
  • Hu H, Luo ML, Desmedt C, Nabavi S, Yadegarynia S, Hong A, Konstantinopoulos PA, Gabrielson E, Hines-Boykin R, Pihan G, Yuan X, Sotirious C, Dittmer DP, Fingeroth JD, Wulf GM. Epstein-Barr Virus Infection of Mammary Epithelial Cells Promotes Malignant Transformation. EBioMedicine 2016. PubMed
  • Hu H, Juvekar A, Lyssiotis CA, Lien EC, Albeck JG, Oh D, Varma G, Hung YP, Ullas S, Lauring J, Seth P, Lundquist MR, Tolan DR, Grant AK, Needleman DJ, Asara JM, Cantley LC, Wulf GM. Phosphoinositide 3-Kinase Regulates Glycolysis through Mobilization of Aldolase from the Actin Cytoskeleton. Cell 2016; 164:433-46. PubMed
  • Luo ML, Gong C, Chen CH, Hu H, Huang P, Zheng M, Yao Y, Wei S, Wulf G, Lieberman J, Zhou XZ, Song E, Lu KP. The Rab2A GTPase promotes breast cancer stem cells and tumorigenesis via Erk signaling activation. Cell Rep 2015. PubMed
  • Luo ML, Gong C, Chen CH, Lee DY, Hu H, Huang P, Yao Y, Guo W, Reinhardt F, Wulf G, Lieberman J, Zhou XZ, Song E, Lu KP. Prolyl isomerase Pin1 acts downstream of miR200c to promote cancer stem-like cell traits in breast cancer. Cancer Res 2014. PubMed
  • Emerling BM, Hurov JB, Poulogiannis G, Tsukazawa KS, Choo-Wing R, Wulf GM, Bell EL, Shim HS, Lamia KA, Rameh LE, Bellinger G, Sasaki AT, Asara JM, Yuan X, Bullock A, Denicola GM, Song J, Brown V, Signoretti S, Cantley LC. Depletion of a putatively druggable class of phosphatidylinositol kinases inhibits growth of p53-null tumors. Cell 2013; 155:844-57. PubMed
  • Israelsen WJ, Dayton TL, Davidson SM, Fiske BP, Hosios AM, Bellinger G, Li J, Yu Y, Sasaki M, Horner JW, Burga LN, Xie J, Jurczak MJ, DePinho RA, Clish CB, Jacks T, Kibbey RG, Wulf GM, Di Vizio D, Mills GB, Cantley LC, Vander Heiden MG. PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell 2013; 155:397-409. PubMed
  • Juvekar A, Burga LN, Hu H, Lunsford EP, Ibrahim YH, Balmañà J, Rajendran A, Papa A, Spencer K, Lyssiotis CA, Nardella C, Pandolfi PP, Baselga J, Scully R, Asara JM, Cantley LC, Wulf GM. Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer. 2012; 2:1048-63. PubMed
  • Morrow PK, Wulf GM, Ensor J, Booser DJ, Moore JA, Flores PR, Xiong Y, Zhang S, Krop IE, Winer EP, Kindelberger DW, Coviello J, Sahin AA, Nuñez R, Hortobagyi GN, Yu D, Esteva FJ. Phase I/II study of trastuzumab in combination with everolimus (RAD001) in patients with HER2-overexpressing metastatic breast cancer who progressed on trastuzumab-based therapy. J Clin Oncol 2011; 29:3126-32. PubMed
  • Yuan TL, Wulf G, Burga L, Cantley LC. Cell-to-cell variability in PI3K protein level regulates PI3K-AKT pathway activity in cell populations. Curr Biol 2011; 21:173-83. PubMed
  • Burga LN, Hu H, Juvekar A, Tung NM, Troyan SL, Hofstatter EW, Wulf GM. Loss of BRCA1 leads to an increase in epidermal growth factor receptor expression in mammary epithelial cells, and epidermal growth factor receptor inhibition prevents estrogen receptor-negative cancers in BRCA1-mutant mice. Breast Cancer Res 2011; 13:R30. PubMed
  • Dohm A, Hasenkamp J, Bertsch HP, Maas JH, Truemper L, Wulf G. Progression of a CD4+/CD56+ blastic plasmacytoid DC neoplasm after initiation of extracorporeal photopheresis in an allogeneic transplant recipient. Bone Marrow Transplant 2010. PubMed
  • Ryo A,Wulf G,Lee TH,Lu KP. Pinning down HER2-ER crosstalk in SMRT regulation. Trends Biochem Sci 2009; 34:162-5. PubMed
  • Burga LN,Tung NM,Troyan SL,Bostina M,Konstantinopoulos PA,Fountzilas H,Spentzos D,Miron A,Yassin YA,Lee BT,Wulf GM. Altered proliferation and differentiation properties of primary mammary epithelial cells from BRCA1 mutation carriers. Cancer Res 2009; 69:1273-8. PubMed
  • Lam PB,Burga LN,Wu BP,Hofstatter EW,Lu KP,Wulf GM. Prolyl isomerase Pin1 is highly expressed in Her2-positive breast cancer and regulates erbB2 protein stability. Mol Cancer 2008; 7:91. PubMed
  • Lu KP, Suizu F, Zhou XZ, Finn G, Lam P, Wulf G. Targeting carcinogenesis: a role for the prolyl isomerase Pin1? Mol Carcinog 2006; 45:397-402. PubMed
  • Pastorino L, Sun A, Lu PJ, Zhou XZ, Balastik M, Finn G, Wulf G, Lim J, Li SH, Li X, Xia W, Nicholson LK, Lu KP. The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-beta production. Nature 2006; 440:528-34. PubMed
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