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Vanderbilt-Ingram Cancer CenterVanderbilt-Ingram Cancer Center

 
Rebecca S.  Cook

Rebecca S. Cook, Ph.D.

Assistant Professor of Cancer Biology
Assistant Professor of Biomedical Engineering
Researcher

Contact Information:

Vanderbilt-Ingram Cancer Center
Rm 759 Preston Research Building
2220 Pierce Avenue
Nashville, TN 37232-6840
615-936-3813
Fax: 615-936-2911

Education
  • Ph.D., University of Cincinnati, Cincinnati, Ohio (1998)
  • B.S., Vanderbilt University, Nashville, Tennessee (1993)
Research Description

Many of the physiologic signaling pathways that contribute to tissue development and function are often comandeered by tumor cells to prmote their own growth and metastasis. It is becoming increasingly clear that signaling pathways necessary for growth of the breast epithelium during puberty and pregnancy, and for breast remodeling after lactation are abnormally activated during various stages of tumor formation and progression. The long-term goal of our research is a greater understanding of these signaling pathways, and how they contribute to both mammary gland physiology and breast cancer.

Much of our research focuses on signaling pathways induced by the ErbB family of receptor tyrosine kinases, which include EGFR, ErbB2, ErbB3, and ErbB4. Evidence suggests that three of these family members, EGFR, ErbB2, and ErbB3, are required for increased growth of the mammary epithelium during puberty and pregnancy. Their pathologic overexpression contributes to breast tumor formation and increased malignancy. Much of our current research examines the specific contributions of ErbB3 to breast cancer progression, and its potential as a therapeutic target in ErbB2-expressing breast cancers.

In contrast, ErbB4 is required for lactational differentiation of the mammary epithelium. The role and prognostic value of ErbB4 in breast cancer remains unclear, and our recently published work is aimed at understanding how ErbB4 expression impacts the behavior of normal mammary epithelial cells. Future studies will build on this work and focus on how ErbB4, and the signaling pathways activated in response to ErbB4, impact growth and progression of mammary tumors.

Finally, remodeling of the mammary gland after lactation ceases, a process known as involution, is a complex process that requires elimination of much of the mammary epithelium, accompanied by a profound level of structural remodling of the mammary stroma. Remodeling of the mammary stroma requires a series of communications between the mammary epithelium and its surrounding stromal environment. Evidence suggests that many of the stromal remodeling events and the signaling pathways that regulate these events are also active in breast tumors, and contribute to the pathology of the disease. Our ongoing research will use models of impaired involution versus sustained involution to determine the impact of involution-specific stromal remodeling events upon homeostasis of the mammary epithelium, and to the growth and metastasis of breast tumors.

Publications
  • Chakrabarty A, Rexer BN, Wang SE, Cook RS, Engelman JA, Arteaga CL. H1047R phosphatidylinositol 3-kinase mutant enhances HER2-mediated transformation by heregulin production and activation of HER3. Oncogene [print-electronic]. 2010 Sep 9/16/2010; 29(37): 5193-203. PMID: 20581867, PMCID: PMC2945381, PII: onc2010257, DOI: 10.1038/onc.2010.257, ISSN: 1476-5594.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/20581867.
  • Zhuang G, Brantley-Sieders DM, Vaught D, Yu J, Xie L, Wells S, Jackson D, Muraoka-Cook R, Arteaga C, Chen J. Elevation of receptor tyrosine kinase EphA2 mediates resistance to trastuzumab therapy. Cancer Res [print-electronic]. 2010 Jan 1/1/2010; 70(1): 299-308. PMID: 20028874, PMCID: PMC3859619, PII: 0008-5472.CAN-09-1845, DOI: 10.1158/0008-5472.CAN-09-1845, ISSN: 1538-7445.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/20028874.
  • Mahajan K, Coppola D, Challa S, Fang B, Chen YA, Zhu W, Lopez AS, Koomen J, Engelman RW, Rivera C, Muraoka-Cook RS, Cheng JQ, Schönbrunn E, Sebti SM, Earp HS, Mahajan NP. Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation. PLoS ONE. 2010; 5(3): e9646. PMID: 20333297, PMCID: PMC2841635, DOI: 10.1371/journal.pone.0009646, ISSN: 1932-6203.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/20333297.
  • Miller TW, Forbes JT, Shah C, Wyatt SK, Manning HC, Olivares MG, Sanchez V, Dugger TC, de Matos Granja N, Narasanna A, Cook RS, Kennedy JP, Lindsley CW, Arteaga CL. Inhibition of mammalian target of rapamycin is required for optimal antitumor effect of HER2 inhibitors against HER2-overexpressing cancer cells. Clin. Cancer Res [print-electronic]. 2009 Dec 12/1/2009; 15(23): 7266-76. PMID: 19934303, PMCID: PMC2787848, PII: 1078-0432.CCR-09-1665, DOI: 10.1158/1078-0432.CCR-09-1665, ISSN: 1078-0432.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/19934303.
  • Muraoka-Cook RS, Sandahl MA, Strunk KE, Miraglia LC, Husted C, Hunter DM, Elenius K, Chodosh LA, Earp HS. ErbB4 splice variants Cyt1 and Cyt2 differ by 16 amino acids and exert opposing effects on the mammary epithelium in vivo. Mol. Cell. Biol [print-electronic]. 2009 Sep; 29(18): 4935-48. PMID: 19596786, PMCID: PMC2738276, PII: MCB.01705-08, DOI: 10.1128/MCB.01705-08, ISSN: 1098-5549.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/19596786.
  • Feng SM, Muraoka-Cook RS, Hunter D, Sandahl MA, Caskey LS, Miyazawa K, Atfi A, Earp HS. The E3 ubiquitin ligase WWP1 selectively targets HER4 and its proteolytically derived signaling isoforms for degradation. Mol. Cell. Biol [print-electronic]. 2009 Feb; 29(3): 892-906. PMID: 19047365, PMCID: PMC2630679, PII: MCB.00595-08, DOI: 10.1128/MCB.00595-08, ISSN: 1098-5549.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/19047365.
  • Muraoka-Cook RS, Sandahl M, Hunter D, Miraglia L, Earp HS. Prolactin and ErbB4/HER4 signaling interact via Janus kinase 2 to induce mammary epithelial cell gene expression differentiation. Mol. Endocrinol [print-electronic]. 2008 Oct; 22(10): 2307-21. PMID: 18653779, PMCID: PMC2582536, PII: me.2008-0055, DOI: 10.1210/me.2008-0055, ISSN: 0888-8809.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/18653779.
  • Muraoka-Cook RS, Feng SM, Strunk KE, Earp HS. ErbB4/HER4: role in mammary gland development, differentiation and growth inhibition. J Mammary Gland Biol Neoplasia [print-electronic]. 2008 Jun; 13(2): 235-46. PMID: 18437540, PMCID: PMC3325098, DOI: 10.1007/s10911-008-9080-x, ISSN: 1083-3021.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/18437540.
  • Brantley-Sieders DM, Zhuang G, Hicks D, Fang WB, Hwang Y, Cates JM, Coffman K, Jackson D, Bruckheimer E, Muraoka-Cook RS, Chen J. The receptor tyrosine kinase EphA2 promotes mammary adenocarcinoma tumorigenesis and metastatic progression in mice by amplifying ErbB2 signaling. J. Clin. Invest. 2008 Jan; 118(1): 64-78. PMID: 18079969, PMCID: PMC2129239, DOI: 10.1172/JCI33154, ISSN: 0021-9738.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/18079969.
  • Feng SM, Sartor CI, Hunter D, Zhou H, Yang X, Caskey LS, Dy R, Muraoka-Cook RS, Earp HS. The HER4 cytoplasmic domain, but not its C terminus, inhibits mammary cell proliferation. Mol. Endocrinol [print-electronic]. 2007 Aug; 21(8): 1861-76. PMID: 17505063, PMCID: PMC2917064, PII: me.2006-0101, DOI: 10.1210/me.2006-0101, ISSN: 0888-8809.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/17505063.
  • Strunk KE, Husted C, Miraglia LC, Sandahl M, Rearick WA, Hunter DM, Earp HS, Muraoka-Cook RS. HER4 D-box sequences regulate mitotic progression and degradation of the nuclear HER4 cleavage product s80HER4. Cancer Res. 2007 Jul 7/15/2007; 67(14): 6582-90. PMID: 17638867, PMCID: PMC2917069, PII: 67/14/6582, DOI: 10.1158/0008-5472.CAN-06-4145, ISSN: 0008-5472.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/17638867.
  • Muraoka-Cook RS, Caskey LS, Sandahl MA, Hunter DM, Husted C, Strunk KE, Sartor CI, Rearick WA, McCall W, Sgagias MK, Cowan KH, Earp HS. Heregulin-dependent delay in mitotic progression requires HER4 and BRCA1. Mol. Cell. Biol. 2006 Sep; 26(17): 6412-24. PMID: 16914727, PMCID: PMC1592831, PII: 26/17/6412, DOI: 10.1128/MCB.01950-05, ISSN: 0270-7306.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/16914727.
  • Muraoka-Cook RS, Sandahl M, Husted C, Hunter D, Miraglia L, Feng SM, Elenius K, Earp HS. The intracellular domain of ErbB4 induces differentiation of mammary epithelial cells. Mol. Biol. Cell [print-electronic]. 2006 Sep; 17(9): 4118-29. PMID: 16837552, PMCID: PMC1556387, PII: E06-02-0101, DOI: 10.1091/mbc.E06-02-0101, ISSN: 1059-1524.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/16837552.
  • Muraoka-Cook RS, Shin I, Yi JY, Easterly E, Barcellos-Hoff MH, Yingling JM, Zent R, Arteaga CL. Activated type I TGFbeta receptor kinase enhances the survival of mammary epithelial cells and accelerates tumor progression. Oncogene [print-electronic]. 2006 Jun 6/8/2006; 25(24): 3408-23. PMID: 16186809, PII: 1208964, DOI: 10.1038/sj.onc.1208964, ISSN: 0950-9232.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/16186809.
  • Cheng N, Bhowmick NA, Chytil A, Gorksa AE, Brown KA, Muraoka R, Arteaga CL, Neilson EG, Hayward SW, Moses HL. Loss of TGF-beta type II receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of TGF-alpha-, MSP- and HGF-mediated signaling networks. Oncogene. 2005 Jul 7/28/2005; 24(32): 5053-68. PMID: 15856015, PMCID: PMC3074577, PII: 1208685, DOI: 10.1038/sj.onc.1208685, ISSN: 0950-9232.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/15856015.
  • Muraoka-Cook RS, Dumont N, Arteaga CL. Dual role of transforming growth factor beta in mammary tumorigenesis and metastatic progression. Clin. Cancer Res. 2005 Jan 1/15/2005; 11(2 Pt 2): 937s-43s. PMID: 15701890, PII: 11/2/937S, ISSN: 1078-0432.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/15701890.
  • Muraoka-Cook RS, Kurokawa H, Koh Y, Forbes JT, Roebuck LR, Barcellos-Hoff MH, Moody SE, Chodosh LA, Arteaga CL. Conditional overexpression of active transforming growth factor beta1 in vivo accelerates metastases of transgenic mammary tumors. Cancer Res. 2004 Dec 12/15/2004; 64(24): 9002-11. PMID: 15604265, PII: 64/24/9002, DOI: 10.1158/0008-5472.CAN-04-2111, ISSN: 0008-5472.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/15604265.
  • Muraoka RS, Koh Y, Roebuck LR, Sanders ME, Brantley-Sieders D, Gorska AE, Moses HL, Arteaga CL. Increased malignancy of Neu-induced mammary tumors overexpressing active transforming growth factor beta1. Mol. Cell. Biol. 2003 Dec; 23(23): 8691-703. PMID: 14612410, PMCID: PMC262670, ISSN: 0270-7306.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/14612410.
  • Brantley DM, Cheng N, Thompson EJ, Lin Q, Brekken RA, Thorpe PE, Muraoka RS, Cerretti DP, Pozzi A, Jackson D, Lin C, Chen J. Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo. Oncogene. 2002 Oct 10/10/2002; 21(46): 7011-26. PMID: 12370823, DOI: 10.1038/sj.onc.1205679, ISSN: 0950-9232.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/12370823.
  • Muraoka RS, Dumont N, Ritter CA, Dugger TC, Brantley DM, Chen J, Easterly E, Roebuck LR, Ryan S, Gotwals PJ, Koteliansky V, Arteaga CL. Blockade of TGF-beta inhibits mammary tumor cell viability, migration, and metastases. J. Clin. Invest. 2002 Jun; 109(12): 1551-9. PMID: 12070302, PMCID: PMC151012, DOI: 10.1172/JCI15234, ISSN: 0021-9738.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/12070302.
  • Muraoka RS, Lenferink AE, Law B, Hamilton E, Brantley DM, Roebuck LR, Arteaga CL. ErbB2/Neu-induced, cyclin D1-dependent transformation is accelerated in p27-haploinsufficient mammary epithelial cells but impaired in p27-null cells. Mol. Cell. Biol. 2002 Apr; 22(7): 2204-19. PMID: 11884607, PMCID: PMC133673, ISSN: 0270-7306.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/11884607.
  • Muraoka RS, Lenferink AE, Simpson J, Brantley DM, Roebuck LR, Yakes FM, Arteaga CL. Cyclin-dependent kinase inhibitor p27(Kip1) is required for mouse mammary gland morphogenesis and function. J. Cell Biol. 2001 May 5/28/2001; 153(5): 917-32. PMID: 11381079, PMCID: PMC2174338, ISSN: 0021-9525.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/11381079.
  • Brantley DM, Chen CL, Muraoka RS, Bushdid PB, Bradberry JL, Kittrell F, Medina D, Matrisian LM, Kerr LD, Yull FE. Nuclear factor-kappaB (NF-kappaB) regulates proliferation and branching in mouse mammary epithelium. Mol. Biol. Cell. 2001 May; 12(5): 1445-55. PMID: 11359934, PMCID: PMC34596, ISSN: 1059-1524.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/11359934.
  • Brantley DM, Yull FE, Muraoka RS, Hicks DJ, Cook CM, Kerr LD. Dynamic expression and activity of NF-kappaB during post-natal mammary gland morphogenesis. Mech. Dev. 2000 Oct; 97(1-2): 149-55. PMID: 11025216, PII: S0925477300004056, ISSN: 0925-4773.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/11025216.
  • Muraoka RS, Bushdid PB, Brantley DM, Yull FE, Kerr LD. Mesenchymal expression of nuclear factor-kappaB inhibits epithelial growth and branching in the embryonic chick lung. Dev. Biol. 2000 Sep 9/15/2000; 225(2): 322-38. PMID: 10985853, PII: S0012-1606(00)99824-5, DOI: 10.1006/dbio.2000.9824, ISSN: 0012-1606.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/10985853.
  • Muraoka RS, Sun WY, Colbert MC, Waltz SE, Witte DP, Degen JL, Friezner Degen SJ. The Ron/STK receptor tyrosine kinase is essential for peri-implantation development in the mouse. J. Clin. Invest. 1999 May; 103(9): 1277-85. PMID: 10225971, PMCID: PMC408470, DOI: 10.1172/JCI6091, ISSN: 0021-9738.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/10225971.
  • Muraoka RS, Waltz SE, Degen SJ. Expression of hepatocyte growth factor-like protein is repressed by retinoic acid and enhanced by cyclic adenosine 3',5'-monophosphate response element-binding protein (CREB)-binding protein (CBP). Endocrinology. 1999 Jan; 140(1): 187-96. PMID: 9886825, DOI: 10.1210/endo.140.1.6441, ISSN: 0013-7227.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/9886825.
  • Margolis PA, Cook RL, Earp JA, Lannon CM, Keyes LL, Klein JD. Factors associated with pediatricians' participation in Medicaid in North Carolina. JAMA. 1992 Apr 4/8/1992; 267(14): 1942-6. PMID: 1296580, ISSN: 0098-7484.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/1296580.