Rebecca S. Cook, Ph.D.
Assistant Professor of Cancer Biology
Vanderbilt-Ingram Cancer Center
Rm 759 Preston Research Building
2220 Pierce Avenue
Nashville, TN 37232-6840
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.
- 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, SchÃ¶nbrunn, E, Sebti, SM, Earp, HS, Mahajan, NP Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation. PLoS One, 5(3), e9646, 2010.
- 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, 70(1), 299-308, 2010.
- 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, 2010.
- 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, 29(18), 4935-48, 2009.
- 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, 15(23), 7266-76, 2009.
- 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, 29(3), 892-906, 2009.
- 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, 13(2), 235-46, 2008.
- Muraoka-Cook, RS, Sandahl, M, Hunter, D, Miraglia, L, Earp, HS Prolactin and ErbB4/HER4 Signaling Interact Via JAK2 to Induce Mammary Epithelial Cell Gene Expression Differentiation. Mol Endocrinol, 2008.
- 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, 118(1), 64-78, 2008.
- 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, 67(14), 6582-90, 2007.
- 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, 21(8), 1861-76, 2007.
- 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, 25(24), 3408-23, 2006.
- 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, 26(17), 6412-24, 2006.
- 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, 17(9), 4118-29, 2006.
- Muraoka-Cook, RS, Dumont, N, Arteaga, CL Dual role of transforming growth factor beta in mammary tumorigenesis and metastatic progression. Clin Cancer Res, 11(2 Pt 2), 937s-43s, 2005.
- 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, 24(32), 5053-68, 2005.
- 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, 64(24), 9002-11, 2004.
- 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, 23(23), 8691-703, 2003.
- 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, 109(12), 1551-9, 2002.
- 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, 22(7), 2204-19, 2002.
- 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, 21(46), 7011-26, 2002.
- 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, 153(5), 917-32, 2001.
- 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, 12(5), 1445-55, 2001.
- 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, 97(1-2), 149-55, 2000.
- 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, 225(2), 322-38, 2000.
- 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, 140(1), 187-96, 1999.
- 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, 103(9), 1277-85, 1999.
- Margolis, PA, Cook, RL, Earp, JA, Lannon, CM, Keyes, LL, Klein, JD Factors associated with pediatricians'' participation in Medicaid in North Carolina. JAMA, 267(14), 1942-6, 1992.