Photo of Peter Sicinski,  MD, PhD

Peter Sicinski, MD, PhD

Dana-Farber Cancer Institute

Dana-Farber Cancer Institute
Phone: (617) 632-5005
Fax: (617) 632-5006


peter_sicinski@dfci.harvard.edu

Peter Sicinski, MD, PhD

Dana-Farber Cancer Institute

EDUCATIONAL TITLES

  • Professor, Genetics, Harvard Medical School

DF/HCC PROGRAM AFFILIATION

Research Abstract

The proliferation of mammalian cells is tightly controlled by numerous external signals. After they are received by the cells, these growth-promoting or growth-inhibitory signals are transmitted to the so-called cell-cycle machinery operating in the nucleus. The cell-cycle machinery is present in every single cell, and it can be thought of as the molecular engine that drives cell proliferation. The key components of this machinery are proteins termed cyclins. Abnormal expression of cyclins is seen in a great number of human cancers. For example, more than 50% of human breast cancers contain highly elevated levels of a particular cyclin protein, termed cyclin D1. Importantly, because agents that antagonize this cyclin have been shown to shut off the proliferation of breast cancer cells grown in vitro, overexpression of cyclin D1 seems to play a causative role in mammary tumorigenesis.



To understand the role played by these various cyclin proteins in normal development and in cancer, we generated several genetically engineered 'knockout' mouse strains lacking different cyclin proteins. We found that each of these proteins is required for proliferation in a very narrow, highly specific sets of tissues. For example, we discovered that cyclin D1-deficient mice develop hormone-insensitive mammary glands. Hence, the normal, physiologic role for cyclin D1 is to drive hormone-induced mammary epithelial proliferation, while overexpression of the very same cyclin plays a causative role in human breast cancers.



We are currently using these knockout strains, and cells derived from them, as tools to study the role of particular cyclin proteins in normal cell proliferation and in oncogenesis of breast cancers, in particular. Moreover, we are generating novel mutant mouse strains that will help explain the role of cell-cycle machinery at the organismal, cellular, and molecular levels.

Publications

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  • Manterola M, Sicinski P, Wolgemuth DJ. E-type cyclins modulate telomere integrity in mammalian male meiosis. Chromosoma 2016; 125:253-64. PubMed
  • Hydbring P, Malumbres M, Sicinski P. Non-canonical functions of cell cycle cyclins and cyclin-dependent kinases. Nat Rev Mol Cell Biol 2016; 17:280-92. PubMed
  • Goel S, Wang Q, Watt AC, Tolaney SM, Dillon DA, Li W, Ramm S, Palmer AC, Yuzugullu H, Varadan V, Tuck D, Harris LN, Wong KK, Liu XS, Sicinski P, Winer EP, Krop IE, Zhao JJ. Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors. Cancer Cell 2016; 29:255-69. PubMed
  • Li N, Fassl A, Chick J, Inuzuka H, Li X, Mansour MR, Liu L, Wang H, King B, Shaik S, Gutierrez A, Ordureau A, Otto T, Kreslavsky T, Baitsch L, Bury L, Meyer CA, Ke N, Mulry KA, Kluk MJ, Roy M, Kim S, Zhang X, Geng Y, Zagozdzon A, Jenkinson S, Gale RE, Linch DC, Zhao JJ, Mullighan CG, Harper JW, Aster JC, Aifantis I, von Boehmer H, Gygi SP, Wei W, Look AT, Sicinski P. Cyclin C is a haploinsufficient tumour suppressor. Nat Cell Biol 2014; 16:1080-91. PubMed
  • Bhalla K, Liu WJ, Thompson K, Anders L, Devarakonda S, Dewi R, Buckley S, Hwang BJ, Polster B, Dorsey SG, Sun Y, Sicinski P, Girnun GD. Cyclin D1 represses gluconeogenesis via inhibition of the transcriptional coactivator PGC1α. Diabetes 2014; 63:3266-78. PubMed
  • Choi YJ, Saez B, Anders L, Hydbring P, Stefano J, Bacon NA, Cook C, Kalaszczynska I, Signoretti S, Young RA, Scadden DT, Sicinski P. D-cyclins repress apoptosis in hematopoietic cells by controlling death receptor Fas and its ligand FasL. Dev Cell 2014; 30:255-67. PubMed
  • Lee Y, Dominy JE, Choi YJ, Jurczak M, Tolliday N, Camporez JP, Chim H, Lim JH, Ruan HB, Yang X, Vazquez F, Sicinski P, Shulman GI, Puigserver P. Cyclin D1-Cdk4 controls glucose metabolism independently of cell cycle progression. Nature 2014. PubMed
  • Naetar N, Soundarapandian V, Litovchick L, Goguen KL, Sablina AA, Bowman-Colin C, Sicinski P, Hahn WC, DeCaprio JA, Livingston DM. PP2A-mediated regulation of Ras signaling in G2 is essential for stable quiescence and normal G1 length. Mol Cell 2014. PubMed
  • Liu P, Begley M, Michowski W, Inuzuka H, Ginzberg M, Gao D, Tsou P, Gan W, Papa A, Kim BM, Wan L, Singh A, Zhai B, Yuan M, Wang Z, Gygi SP, Lee TH, Lu KP, Toker A, Pandolfi PP, Asara JM, Kirschner MW, Sicinski P, Cantley L, Wei W. Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus. Nature 2014; 508:541-5. PubMed
  • Martinerie L, Manterola M, Chung SS, Panigrahi SK, Weisbach M, Vasileva A, Geng Y, Sicinski P, Wolgemuth DJ. Mammalian E-type cyclins control chromosome pairing, telomere stability and CDK2 localization in male meiosis. PLoS Genet. 2014; 10:e1004165. PubMed
  • Narasimha AM, Kaulich M, Shapiro GS, Choi YJ, Sicinski P, Dowdy SF. Cyclin D activates the Rb tumor suppressor by mono-phosphorylation. Elife 2014. PubMed
  • Geng Y, Sicinski P. Differences in regulation and function of E-cyclins in human cancer cells. Cell Cycle 2013; 12:1165. PubMed
  • Choi YJ, Sicinski P. Unexpected outcomes of CDK4/6 inhibition. 2013; 4:176-7. PubMed
  • Nakaya T, Ishiguro KI, Belzil C, Rietsch AM, Yu Q, Mizuno SI, Bronson RT, Geng Y, Nguyen MD, Akashi K, Sicinski P, Nakatani Y. p600 Plays Essential Roles in Fetal Development. PLoS ONE 2013; 8:e66269. PubMed
  • Kreslavsky T, Gleimer M, Miyazaki M, Choi Y, Gagnon E, Murre C, Sicinski P, von Boehmer H. β-Selection-induced proliferation is required for αβ T cell differentiation. Immunity 2012; 37:840-53. PubMed
  • Chen HZ, Ouseph MM, Li J, Pécot T, Chokshi V, Kent L, Bae S, Byrne M, Duran C, Comstock G, Trikha P, Mair M, Senapati S, Martin CK, Gandhi S, Wilson N, Liu B, Huang YW, Thompson JC, Raman S, Singh S, Leone M, Machiraju R, Huang K, Mo X, Fernandez S, Kalaszczynska I, Wolgemuth DJ, Sicinski P, Huang T, Jin V, Leone G. Canonical and atypical E2Fs regulate the mammalian endocycle. Nat Cell Biol 2012; 14:1192-202. PubMed
  • Choi YJ, Li X, Hydbring P, Sanda T, Stefano J, Christie AL, Signoretti S, Look AT, Kung AL, von Boehmer H, Sicinski P. The requirement for cyclin D function in tumor maintenance. Cancer Cell 2012; 22:438-51. PubMed
  • Sankaran VG, Ludwig LS, Sicinska E, Xu J, Bauer DE, Eng JC, Patterson HC, Metcalf RA, Natkunam Y, Orkin SH, Sicinski P, Lander ES, Lodish HF. Cyclin D3 coordinates the cell cycle during differentiation to regulate erythrocyte size and number. Genes Dev 2012; 26:2075-87. PubMed
  • Jirawatnotai S, Hu Y, Livingston DM, Sicinski P. Proteomic identification of a direct role for cyclin d1 in DNA damage repair. Cancer Res 2012; 72:4289-93. PubMed
  • Odajima J, Kalaszczynska I, Sicinski P. Cyclins A and E trigger DNA damage. Cell Cycle 2010; 9:1231-2. PubMed
  • Cole AM, Myant K, Reed KR, Ridgway RA, Athineos D, Van den Brink GR, Muncan V, Clevers H, Clarke AR, Sicinski P, Sansom OJ. Cyclin D2-cyclin-dependent kinase 4/6 is required for efficient proliferation and tumorigenesis following Apc loss. Cancer Res 2010; 70:8149-58. PubMed
  • Peled JU, Yu JJ, Venkatesh J, Bi E, Ding BB, Krupski-Downs M, Shaknovich R, Sicinski P, Diamond B, Scharff MD, Ye BH. Requirement for cyclin D3 in germinal center formation and function. Cell Res 2010; 20:631-46. PubMed
  • Bienvenu F, Jirawatnotai S, Elias JE, Meyer CA, Mizeracka K, Marson A, Frampton GM, Cole MF, Odom DT, Odajima J, Geng Y, Zagozdzon A, Jecrois M, Young RA, Liu XS, Cepko CL, Gygi SP, Sicinski P. Transcriptional role of cyclin D1 in development revealed by a genetic-proteomic screen. Nature 2010; 463:374-8. PubMed
  • Nevzorova YA,Tschaharganeh D,Gassler N,Geng Y,Weiskirchen R,Sicinski P,Trautwein C,Liedtke C. Aberrant Cell Cycle Progression and Endoreplication in Regenerating Livers of Mice That Lack a Single E-Type Cyclin. Gastroenterology 2009; 137:691-703, 703.e1-6. PubMed
  • Kalaszczynska I, Geng Y, Iino T, Mizuno S, Choi Y, Kondratiuk I, Silver DP, Wolgemuth DJ, Akashi K, Sicinski P. Cyclin A is redundant in fibroblasts but essential in hematopoietic and embryonic stem cells. Cell 2009; 138:352-65. PubMed
  • Francis RE, Myatt SS, Krol J, Hartman J, Peck B, McGovern UB, Wang J, Guest SK, Filipovic A, Gojis O, Palmieri C, Peston D, Shousha S, Yu Q, Sicinski P, Coombes RC, Lam EW. FoxM1 is a downstream target and marker of HER2 overexpression in breast cancer. Int J Oncol 2009; 35:57-68. PubMed
  • Joshi I,Minter LM,Telfer J,Demarest RM,Capobianco AJ,Aster JC,Sicinski P,Fauq A,Golde TE,Osborne BA. Notch signaling mediates G1/S cell-cycle progression in T cells via cyclin D3 and its dependent kinases. Blood 2008; 113:1689-98. PubMed
  • Zeng L,Geng Y,Tretiakova M,Yu X,Sicinski P,Kroll TG. Peroxisome proliferator-activated receptor-delta induces cell proliferation by a cyclin E1-dependent mechanism and is up-regulated in thyroid tumors. Cancer Res 2008; 68:6578-86. PubMed
  • Landis MW, Brown NE, Baker GL, Shifrin A, Das M, Geng Y, Sicinski P, Hinds PW. The LxCxE pRb interaction domain of cyclin D1 is dispensable for murine development. Cancer Res 2007; 67:7613-20. PubMed
  • Sicinski P, Zacharek S, Kim C. Duality of p27Kip1 function in tumorigenesis. Genes Dev 2007; 21:1703-6. PubMed
  • Geng Y, Lee YM, Welcker M, Swanger J, Zagozdzon A, Winer JD, Roberts JM, Kaldis P, Clurman BE, Sicinski P. Kinase-independent function of cyclin E. Mol Cell 2007; 25:127-39. PubMed
  • Sicinska E, Lee YM, Gits J, Shigematsu H, Yu Q, Rebel VI, Geng Y, Marshall CJ, Akashi K, Dorfman DM, Touw IP, Sicinski P. Essential role for cyclin D3 in granulocyte colony-stimulating factor-driven expansion of neutrophil granulocytes. Mol Cell Biol 2006; 26:8052-60. PubMed
  • Lee YM, Sicinski P. Targeting cyclins and cyclin-dependent kinases in cancer: lessons from mice, hopes for therapeutic applications in human. Cell Cycle 2006; 5:2110-4. PubMed
  • Isaac CE, Francis SM, Martens AL, Julian LM, Seifried LA, Erdmann N, Binn. The retinoblastoma protein regulates pericentric heterochromatin. Mol Cell Biol 2006; 26:3659-71. PubMed
  • Cooper AB, Sawai CM, Sicinska E, Powers SE, Sicinski P, Clark MR, Aifantis I. A unique function for cyclin D3 in early B cell development. Nat Immunol 2006; 7:489-97. PubMed
  • Yu Q, Sicinska E, Geng Y, Ahnstr. Requirement for CDK4 kinase function in breast cancer. Cancer Cell 2006; 9:23-32. PubMed
  • Landis MW, Pawlyk BS, Li T, Sicinski P, Hinds PW. Cyclin D1-dependent kinase activity in murine development and mammary tumorigenesis. Cancer Cell 2006; 9:13-22. PubMed
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