Photo of Patricia K. Donahoe,  MD

Patricia K. Donahoe, MD

Massachusetts General Hospital

Massachusetts General Hospital
Phone: (617) 724-1600
Fax: (617) 726-5057


pdonahoe@partners.org

Patricia K. Donahoe, MD

Massachusetts General Hospital

EDUCATIONAL TITLES

  • Marshall K. Bartlett Distinguished Professor of Surgery, Surgery, Harvard Medical School
  • Director, Pediatric Surgical Research Laboratories, Pediatric Surgical Services, Massachusetts General Hospital

DF/HCC PROGRAM AFFILIATION

Research Abstract

Our laboratory studies the molecular mechanisms by which TGFB family proteins suppress growth, focusing on Mullerian Inhibiting Substance (MIS) as a model. After purifying MIS protein and cloning its gene, we cloned the genes for its type I and type II receptors and a number of other receptors of this transmembrane serine/threonine kinase family, and used homologous recombination to uncover their early embryonic function using human ovarian and breast carcinomas as targets for MIS, the laboratory discovered that MIS produced G1 arrest and apoptosis by inducing p16 in ovarian cancer, and by inducing NFKB and regulating the specific IEX-1S isoform in breast cancer cell lines. Preclinical trials of MIS are underway in preparation for phase I clinical trials in human ovarian cancer patients.

We also study the molecular mechanisms of sex differentiation and of foregut development to correct congenital anomalies of the trachea and esophagus. As she and her colleagues search for gene defects causing congenital anomalies, they hope to design in utero pharmacologic therapies to reduce the severity of the abnormalities at birth.

Publications

Powered by Harvard Catalyst
  • Chung YJ, Kim HJ, Park SH, Yoon JH, Kim MR, Nam SW, MacLaughlin DT, Donahoe PK, Kim JH. Transcriptome analysis reveals that M端llerian inhibiting substance regulates signaling pathways that contribute to endometrial carcinogenesis. Int J Oncol 2015; 46:2039-46. PubMed
  • Kim JH, MacLaughlin DT, Donahoe PK. M端llerian inhibiting substance/anti-M端llerian hormone: A novel treatment for gynecologic tumors. Obstet Gynecol Sci 2014; 57:343-57. PubMed
  • Park JH, Tanaka Y, Arango NA, Zhang L, Benedict LA, Roh MI, Donahoe PK, Teixeira JM. Induction of WNT inhibitory factor 1 expression by M端llerian inhibiting substance/antiMullerian hormone in the M端llerian duct mesenchyme is linked to M端llerian duct regression. Dev Biol 2014; 386:227-36. PubMed
  • Namkung J, Song JY, Jo HH, Kim MR, Lew YO, Donahoe PK, MacLaughlin DT, Kim JH. Mullerian inhibiting substance induces apoptosis of human endometrial stromal cells in endometriosis. J Clin Endocrinol Metab 2012; 97:3224-30. PubMed
  • Chang HL, Pieretti-Vanmarcke R, Nicolaou F, Li X, Wei X, MacLaughlin DT, Donahoe PK. Mullerian inhibiting substance inhibits invasion and migration of epithelial cancer cell lines. Gynecol Oncol 2010; 120:128-34. PubMed
  • Wei X, Dombkowski D, Meirelles K, Pieretti-Vanmarcke R, Szotek PP, Chang HL, Preffer FI, Mueller PR, Teixeira J, Maclaughlin DT, Donahoe PK. Mullerian inhibiting substance preferentially inhibits stem/progenitors in human ovarian cancer cell lines compared with chemotherapeutics. Proc Natl Acad Sci U S A 2010; 107:18874-9. PubMed
  • MacLaughlin DT, Donahoe PK. M端llerian inhibiting substance/anti-M端llerian hormone: a potential therapeutic agent for human ovarian and other cancers. Future Oncol 2010; 6:391-405. PubMed
  • Papakostas TD, Pieretti-Vanmarcke R, Nicolaou F, Thanos A, Trichonas G, Koufomichali X, Anago K, Donahoe PK, Teixeira J, MacLaughlin DT, Vavvas D. Development of an efficiently cleaved, bioactive, highly pure FLAG-tagged recombinant human Mullerian Inhibiting Substance. Protein Expr Purif 2010; 70:32-8. PubMed
  • Chang HL, Senaratne TN, Zhang L, Szotek PP, Stewart E, Dombkowski D, Preffer F, Donahoe PK, Teixeira J. Uterine leiomyomas exhibit fewer stem/progenitor cell characteristics when compared with corresponding normal myometrium. Reprod Sci 2010; 17:158-67. PubMed
  • Hayashida T, Takahashi F, Chiba N, Brachtel E, Takahashi M, Godin-Heymann N, Gross KW, Vivanco MM, Wijendran V, Shioda T, Sgroi D, Donahoe PK, Maheswaran S. HOXB9, a gene overexpressed in breast cancer, promotes tumorigenicity and lung metastasis. Proc Natl Acad Sci U S A 2010; 107:1100-5. PubMed
  • Fujino A,Arango NA,Zhan Y,Manganaro TF,Li X,MacLaughlin DT,Donahoe PK. Cell migration and activated PI3K/AKT-directed elongation in the developing rat Mullerian duct. Dev Biol 2008; 325:351-62. PubMed
  • Lage K,Hansen NT,Karlberg EO,Eklund AC,Roque FS,Donahoe PK,Szallasi Z,Jensen TS,Brunak S. A large-scale analysis of tissue-specific pathology and gene expression of human disease genes and complexes. Proc Natl Acad Sci U S A 2008; 105:20870-5. PubMed
  • Szotek PP,Chang HL,Brennand K,Fujino A,Pieretti-Vanmarcke R,Lo Celso C,Dombkowski D,Preffer F,Cohen KS,Teixeira J,Donahoe PK. Normal ovarian surface epithelial label-retaining cells exhibit stem/progenitor cell characteristics. Proc Natl Acad Sci U S A 2008; 105:12469-73. PubMed
  • Kantarci S,Ragge NK,Thomas NS,Robinson DO,Noonan KM,Russell MK,Donnai D,Raymond FL,Walsh CA,Donahoe PK,Pober BR. Donnai-Barrow syndrome (DBS/FOAR) in a child with a homozygous LRP2 mutation due to complete chromosome 2 paternal isodisomy. Am J Med Genet A 2008; 146A:1842-7. PubMed
  • Renlund N, Pieretti-Vanmarcke R, O'Neill FH, Zhang L, Donahoe PK, Teixeira J. c-Jun N-terminal kinase inhibitor II (SP600125) activates Mullerian inhibiting substance type II receptor-mediated signal transduction. Endocrinology 2007; 149:108-15. PubMed
  • Kantarci S, Donahoe PK. Congenital diaphragmatic hernia (CDH) etiology as revealed by pathway genetics. Am J Med Genet C Semin Med Genet 2007; 145:217-26. PubMed
  • Szotek PP, Chang HL, Zhang L, Preffer F, Dombkowski D, Donahoe PK, Teixeira J. Adult mouse myometrial label-retaining cells divide in response to gonadotropin stimulation. Stem Cells 2007; 25:1317-25. PubMed
  • Gupta V, Yeo G, Kawakubo H, Rangnekar V, Ramaswamy P, Hayashida T, MacLaughlin DT, Donahoe PK, Maheswaran S. Mullerian-inhibiting substance induces Gro-beta expression in breast cancer cells through a nuclear factor-kappaB-dependent and Smad1-dependent mechanism. Cancer Res 2007; 67:2747-56. PubMed
  • Pieretti-Vanmarcke R, Donahoe PK, Pearsall LA, Dinulescu DM, Connolly DC, Halpern EF, Seiden MV, MacLaughlin DT. Mullerian Inhibiting Substance enhances subclinical doses of chemotherapeutic agents to inhibit human and mouse ovarian cancer. Proc Natl Acad Sci U S A 2006; 103:17426-31. PubMed
  • Arango NA, Huang TT, Fujino A, Pieretti-Vanmarcke R, Donahoe PK. Expression analysis and evolutionary conservation of the mouse germ cell-specific D6Mm5e gene. Dev Dyn 2006; 235:2613-9. PubMed
  • Szotek PP, Pieretti-Vanmarcke R, Masiakos PT, Dinulescu DM, Connolly D, Foster R, Dombkowski D, Preffer F, Maclaughlin DT, Donahoe PK. Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness. Proc Natl Acad Sci U S A 2006; 103:11154-9. PubMed
  • Zhan Y, Fujino A, MacLaughlin DT, Manganaro TF, Szotek PP, Arango NA, Teixeira J, Donahoe PK. Mlerian inhibiting substance regulates its receptor/SMAD signaling and causes mesenchymal transition of the coelomic epithelial cells early in Mlerian duct regression. Development 2006; 133:2359-69. PubMed
  • Donahoe PK. Genomic approaches to surgical diseases: 21st annual Samuel Jason Mixter lecture. Arch Surg 2006; 141:409-13. PubMed
  • Pieretti-Vanmarcke R, Donahoe PK, Szotek P, Manganaro T, Lorenzen MK, Lorenzen J, Connolly DC, Halpern EF, MacLaughlin DT. Recombinant human Mullerian inhibiting substance inhibits long-term growth of MIS type II receptor-directed transgenic mouse ovarian cancers in vivo. Clin Cancer Res 2006; 12:1593-8. PubMed
  • Arango NA, Szotek PP, Manganaro TF, Oliva E, Donahoe PK, Teixeira J. Conditional deletion of beta-catenin in the mesenchyme of the developing mouse uterus results in a switch to adipogenesis in the myometrium. Dev Biol 2005; 288:276-83. PubMed
  • Wang PY, Koishi K, McGeachie AB, Kimber M, Maclaughlin DT, Donahoe PK, McLennan IS. Mullerian inhibiting substance acts as a motor neuron survival factor in vitro. Proc Natl Acad Sci U S A 2005; 102:16421-5. PubMed
  • Gupta V, Carey J, Kawakubo H, Muzikansky A, Green J, Donahoe PK, MacLaughlin DT, Maheswaran S. Mullerian Inhibiting Substance suppresses tumor grown in the C3(1)T antigen transgenic mouse mammary carcinoma model. Proc Natl Acad Sci U S A 2005; 102:3219-3224.
  • Lee MM, Misra M, Donahoe PK, MacLaughlin DT. MIS/AMH in the assessment of cryptorchidism and intersex conditions. Mol Cell Endocrinol 2003; 211:91-8. PubMed
  • Hoshiya M, Christian BP, Cromie WJ, Kim H, Zhan Y, MacLaughlin DT, Donahoe PK. Persistent Mullerian duct syndrome caused by both a 27-bp deletion and a novel splice mutation in the MIS type II receptor gene. Birth Defects Res A Clin Mol Teratol 2004; 67:868-74. PubMed
  • Dasgupta R, Schnitzer JJ, Hendren WH, Donahoe PK. Congenital adrenal hyperplasia: surgical considerations required to repair a 46,XX patient raised as a boy. J Pediatr Surg 2003; 38:1269-73. PubMed
  • Madsusmita M, MacLaughlin DT, Donahoe PK, Lee MM. The Role of Mlerian Inhibiting Substance in the Evaluation of Phenotypic Female Patients with Mild Degrees of Virilization . Journal of Endocrinology and Metabolism. 2003.
  • Misra M, MacLaughlin DT, Donahoe PK, Lee MM. The role of Mlerian inhibiting substance in the evaluation of phenotypic female patients with mild degrees of virilization. J Clin Endocrinol Metab 2003; 88:787-92. PubMed
  • Laurich VM, Trbovich AM, O'Neill FH, Houk CP, Sluss PM, Payne AH, Donahoe PK, Teixeira J. Mlerian inhibiting substance blocks the protein kinase A-induced expression of cytochrome p450 17alpha-hydroxylase/C(17-20) lyase mRNA in a mouse Leydig cell line independent of cAMP responsive element binding protein phosphorylation. Endocrinology 2002; 143:3351-60. PubMed
  • Madsusmita M, MacLaughlin D, Donohoe P, Lee MM. Measurement of Mullerian Inhibiting Substance Facilitates Management of Boys with Microphallus and Cryptorchidism Harrison's Principles of Internal Medicine. 2002; 87:3598-3602.
  • Stephen AE, Pearsall LA, Christian BP, Donahoe PK, Vacanti JP, MacLaughlin DT. Highly purified mlerian inhibiting substance inhibits human ovarian cancer in vivo. Clin Cancer Res 2002; 8:2640-6. PubMed
  • Segev DL, Hoshiya Y, Hoshiya M, Tran TT, Carey JL, Stephen AE, MacLaughlin DT, Donahoe PK, Maheswaran S. Mullerian-inhibiting substance regulates NF-kappa B signaling in the prostate in vitro and in vivo. Proc Natl Acad Sci U S A 2002; 99:239-44. PubMed
  • Lorenzo HK, Teixeira J, Pahlavan N, Laurich VM, Donahoe PK, MacLaughlin DT. New approaches for high-yield purification of Mlerian inhibiting substance improve its bioactivity. J Chromatogr B Analyt Technol Biomed Life Sci 2002; 766:89-98. PubMed
  • Teixeira J, Maheswaran S, Donahoe PK. Mlerian inhibiting substance: an instructive developmental hormone with diagnostic and possible therapeutic applications. Endocr Rev 2001; 22:657-74. PubMed
  • Sriraman V, Niu E, Matias JR, Donahoe PK, MacLaughlin DT, Hardy MP, Lee MM. Mlerian inhibiting substance inhibits testosterone synthesis in adult rats. J Androl 2001; 22:750-8. PubMed
  • Segev DL, Hoshiya Y, Stephen AE, Hoshiya M, Tran TT, MacLaughlin DT, Donahoe PK, Maheswaran S. Mullerian inhibiting substance regulates NFkappaB signaling and growth of mammary epithelial cells in vivo. J Biol Chem 2001; 276:26799-806. PubMed
  • Clarke TR, Hoshiya Y, Yi SE, Liu X, Lyons KM, Donahoe PK. Mlerian inhibiting substance signaling uses a bone morphogenetic protein (BMP)-like pathway mediated by ALK2 and induces SMAD6 expression. Mol Endocrinol 2001; 15:946-59. PubMed
  • Stephen AE, Masiakos PT, Segev DL, Vacanti JP, Donahoe PK, MacLaughlin DT. Tissue-engineered cells producing complex recombinant proteins inhibit ovarian cancer in vivo. Proc Natl Acad Sci U S A 2001; 98:3214-9. PubMed
  • Trbovich AM, Sluss PM, Laurich VM, O'Neill FH, MacLaughlin DT, Donahoe PK, Teixeira J. Mlerian Inhibiting Substance lowers testosterone in luteinizing hormone-stimulated rodents. Proc Natl Acad Sci U S A 2001; 98:3393-7. PubMed
  • Ukiyama E, Jancso-Radek A, Li B, Milos L, Zhang W, Phillips NB, Morikawa N, King CY, Chan G, Haqq CM, Radek JT, Poulat F, Donahoe PK, Weiss MA. SRYand architectural gene regulation: the kinetic stability of a bent protein-DNA complex can regulate its transcriptional potency. Mol Endocrinol 2001; 15:363-77. PubMed
  • Ha TU, Segev DL, Barbie D, Masiakos PT, Tran TT, Dombkowski D, Glander M, Clarke TR, Lorenzo HK, Donahoe PK, Maheswaran S. Mullerian inhibiting substance inhibits ovarian cell growth through an Rb-independent mechanism. J Biol Chem 2000; 275:37101-9. PubMed
  • Morikawa N, Clarke TR, Novina CD, Watanabe K, Haqq C, Weiss M, Roy AL, Donahoe PK. Human Mlerian-inhibiting substance promoter contains a functional TFII-I-binding initiator. Biol Reprod 2000; 63:1075-83. PubMed
  • Segev DL, Ha TU, Tran TT, Kenneally M, Harkin P, Jung M, MacLaughlin DT, Donahoe PK, Maheswaran S. Mullerian inhibiting substance inhibits breast cancer cell growth through an NFkappa B-mediated pathway. J Biol Chem 2000; 275:28371-9. PubMed
  • Oh SP, Seki T, Goss KA, Imamura T, Yi Y, Donahoe PK, Li L, Miyazono K, ten Dijke P, Kim S, Li E. Activin receptor-like kinase 1 modulates transforming growth factor-beta 1 signaling in the regulation of angiogenesis. Proc Natl Acad Sci U S A 2000; 97:2626-31. PubMed
  • Watanabe K, Clarke TR, Lane AH, Wang X, Donahoe PK. Endogenous expression of Mlerian inhibiting substance in early postnatal rat sertoli cells requires multiple steroidogenic factor-1 and GATA-4-binding sites. Proc Natl Acad Sci U S A 2000; 97:1624-9. PubMed
  • Teixeira J, Kehas DJ, Antun R, Donahoe PK. Transcriptional regulation of the rat Mlerian inhibiting substance type II receptor in rodent Leydig cells. Proc Natl Acad Sci U S A 1999; 96:13831-8. PubMed
  • Masiakos PT, MacLaughlin DT, Maheswaran S, Teixeira J, Fuller AF, Shah PC, Kehas DJ, Kenneally MK, Dombkowski DM, Ha TU, Preffer FI, Donahoe PK. Human ovarian cancer, cell lines, and primary ascites cells express the human Mullerian inhibiting substance (MIS) type II receptor, bind, and are responsive to MIS. Clin Cancer Res 1999; 5:3488-99. PubMed
  • Teixeira J, Fynn-Thompson E, Payne AH, Donahoe PK. Mlerian-inhibiting substance regulates androgen synthesis at the transcriptional level. Endocrinology 1999; 140:4732-8. PubMed
  • Lane AH, Lee MM, Fuller AF, Kehas DJ, Donahoe PK, MacLaughlin DT. Diagnostic utility of Mlerian inhibiting substance determination in patients with primary and recurrent granulosa cell tumors. Gynecol Oncol 1999; 73:51-5. PubMed
  • Haqq CM, Donahoe PK. Regulation of sexual dimorphism in mammals. Physiol Rev 1998; 78:1-33. PubMed
  • Teixeira J, He WW, Shah PC, Morikawa N, Lee MM, Catlin EA, Hudson PL, Wing J, Maclaughlin DT, Donahoe PK. Developmental expression of a candidate mlerian inhibiting substance type II receptor. Endocrinology 1996; 137:160-5. PubMed
Hide