Dana M. Brantley-Sieders, Ph.D.

Assistant Professor

dana.brantley@vanderbilt.edu

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Faculty Appointments
Assistant Professor of Medicine
Education
Ph.D., Cell Biology, Vanderbilt University, Nashville, TennesseeB.A., Biology, Maryville College, Maryville, Tennessee
Office Address
T-3107A MCN, 1161 21st Avenue South
Nashville, TN 37232-2363
Research Description
Our research program focuses on molecular mechanisms that regulate breast tumor growth, tumor angiogenesis, and host-tumor interactions. Members of the Eph family of receptor tyrosine kinases regulate cell growth/survival, motility, and angiogenic remodeling during embryogenesis. More recently, several members of this family have been linked to tumor progression and neovascularization, including breast cancer.

Overexpression of one family member in particular, EphA2, correlates negatively with overall and recurrence-free survival in breast cancer patients. Our laboratory along with others has linked EphA2 signaling to Erk-dependent growth and Rac-dependent invasion in cell culture and animal models of breast cancer, as well as neovascularization and Herceptin-resistance. Moreover, EphA2 physically and functionally interacts with EGF receptor family members, including EGFR and HER2, in the context of breast cancer. More recently, we found EphA2 expression levels are highest within the Triple negative/basal-like subtype of breast cancer. Thus, EphA2 represents a new molecular target for cancer therapy, especially given its simultaneous influence on both tumor cells and the blood vessels within the surrounding microenvironment.

Ongoing studies in the laboratory focus on:

1. The role of EphA2 ligand-independent signaling in lipid metabolism in the context of breast cancer
2. The role of EphA2 signaling in Triple Negative/basal-like breast cancer growth and invasion
3. The role of EphA2 in angiocrine-mediated breast cancer growth and invasion
Research Keywords
Molecular mechanisms that regulate mammary epithelial morphogenesis, breast cancer, and host-tumor interactions
Publications
Song W, Ma Y, Wang J, Brantley-Sieders D, Chen J. JNK signaling mediates EPHA2-dependent tumor cell proliferation, motility, and cancer stem cell-like properties in non-small cell lung cancer. Cancer Res [print-electronic]. 2014 May 5/1/2014; 74(9): 2444-54. PMID: 24607842, PMCID: PMC4008716, PII: 0008-5472.CAN-13-2136, DOI: 10.1158/0008-5472.CAN-13-2136, ISSN: 1538-7445.

Stanford JC, Young C, Hicks D, Owens P, Williams A, Vaught DB, Morrison MM, Lim J, Williams M, Brantley-Sieders DM, Balko JM, Tonetti D, Earp HS 3rd, Cook RS.. Efferocytosis produces a prometastatic landscape during postpartum mammary gland involution. 2014.

Amato KR, Wang S, Hastings AK, Youngblood VM, Santapuram PR, Chen H, Cates JM, Colvin DC, Ye F, Brantley-Sieders DM, Cook RS, Tan L, Gray NS, Chen J.. Genetic and pharmacologic inhibition of EPHA2 promotes apoptosis in NSCLC. 2014.

Zhuang G, Song W, Amato K, Hwang Y, Lee K, Boothby M, Ye F, Guo Y, Shyr Y, Lin L, Carbone DP, Brantley-Sieders DM, Chen J. Effects of cancer-associated EPHA3 mutations on lung cancer. J. Natl. Cancer Inst [print-electronic]. 2012 Aug 8/8/2012; 104(15): 1182-97. PMID: 22829656, PMCID: PMC3611812, PII: djs297, DOI: 10.1093/jnci/djs297, ISSN: 1460-2105.

Brantley-Sieders DM. Clinical relevance of Ephs and ephrins in cancer: lessons from breast, colorectal, and lung cancer profiling. Semin. Cell Dev. Biol [print-electronic]. 2012 Feb; 23(1): 102-8. PMID: 22040912, PMCID: PMC3288332, PII: S1084-9521(11)00202-3, DOI: 10.1016/j.semcdb.2011.10.014, ISSN: 1096-3634.

Brantley-Sieders DM, Fan KH, Deming-Halverson SL, Shyr Y, Cook RS. Local breast cancer spatial patterning: a tool for community health resource allocation to address local disparities in breast cancer mortality. PLoS ONE [print-electronic]. 2012; 7(9): e45238. PMID: 23028869, PMCID: PMC3460936, PII: PONE-D-12-12178, DOI: 10.1371/journal.pone.0045238, ISSN: 1932-6203.

Rao M, Song W, Jiang A, Shyr Y, Lev S, Greenstein D, Brantley-Sieders D, Chen J. VAMP-associated protein B (VAPB) promotes breast tumor growth by modulation of Akt activity. PLoS ONE [print-electronic]. 2012; 7(10): e46281. PMID: 23049696, PMCID: PMC3462209, PII: PONE-D-12-16139, DOI: 10.1371/journal.pone.0046281, ISSN: 1932-6203.

Brantley-Sieders DM, Dunaway CM, Rao M, Short S, Hwang Y, Gao Y, Li D, Jiang A, Shyr Y, Wu JY, Chen J. Angiocrine factors modulate tumor proliferation and motility through EphA2 repression of Slit2 tumor suppressor function in endothelium. Cancer Res [print-electronic]. 2011 Feb 2/1/2011; 71(3): 976-87. PMID: 21148069, PMCID: PMC3032824, PII: 0008-5472.CAN-10-3396, DOI: 10.1158/0008-5472.CAN-10-3396, ISSN: 1538-7445.

Dunaway CM, Hwang Y, Lindsley CW, Cook RS, Wu JY, Boothby M, Chen J, Brantley-Sieders DM. Cooperative signaling between Slit2 and Ephrin-A1 regulates a balance between angiogenesis and angiostasis. Mol. Cell. Biol [print-electronic]. 2011 Feb; 31(3): 404-16. PMID: 21135133, PMCID: PMC3028625, PII: MCB.00667-10, DOI: 10.1128/MCB.00667-10, ISSN: 1098-5549.

Brantley-Sieders DM, Jiang A, Sarma K, Badu-Nkansah A, Walter DL, Shyr Y, Chen J. Eph/ephrin profiling in human breast cancer reveals significant associations between expression level and clinical outcome. PLoS ONE [print-electronic]. 2011; 6(9): e24426. PMID: 21935409, PMCID: PMC3174170, PII: PONE-D-11-14906, DOI: 10.1371/journal.pone.0024426, ISSN: 1932-6203.

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.

Brantley-Sieders DM, Zhuang G, Vaught D, Freeman T, Hwang Y, Hicks D, Chen J. Host deficiency in Vav2/3 guanine nucleotide exchange factors impairs tumor growth, survival, and angiogenesis in vivo. Mol. Cancer Res [print-electronic]. 2009 May; 7(5): 615-23. PMID: 19435813, PMCID: PMC2739740, PII: 1541-7786.MCR-08-0401, DOI: 10.1158/1541-7786.MCR-08-0401, ISSN: 1541-7786.

Vaught D, Chen J, Brantley-Sieders DM. Regulation of mammary gland branching morphogenesis by EphA2 receptor tyrosine kinase. Mol. Biol. Cell [print-electronic]. 2009 May; 20(10): 2572-81. PMID: 19321667, PMCID: PMC2682598, PII: E08-04-0378, DOI: 10.1091/mbc.E08-04-0378, ISSN: 1939-4586.

Li B, Vincent A, Cates J, Brantley-Sieders DM, Polk DB, Young PP. Low levels of tumor necrosis factor alpha increase tumor growth by inducing an endothelial phenotype of monocytes recruited to the tumor site. Cancer Res. 2009 Jan 1/1/2009; 69(1): 338-48. PMID: 19118019, PMCID: PMC2651676, PII: 69/1/338, DOI: 10.1158/0008-5472.CAN-08-1565, ISSN: 1538-7445.

Fang WB, Brantley-Sieders DM, Hwang Y, Ham AJ, Chen J. Identification and functional analysis of phosphorylated tyrosine residues within EphA2 receptor tyrosine kinase. J. Biol. Chem [print-electronic]. 2008 Jun 6/6/2008; 283(23): 16017-26. PMID: 18387945, PMCID: PMC2414276, PII: M709934200, DOI: 10.1074/jbc.M709934200, ISSN: 0021-9258.

Vaught D, Brantley-Sieders DM, Chen J. Eph receptors in breast cancer: roles in tumor promotion and tumor suppression. Breast Cancer Res [print-electronic]. 2008; 10(6): 217. PMID: 19144211, PMCID: PMC2656900, PII: bcr2207, DOI: 10.1186/bcr2207, ISSN: 1465-542X.

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.

Brantley-Sieders DM, Fang WB, Hwang Y, Hicks D, Chen J. Ephrin-A1 facilitates mammary tumor metastasis through an angiogenesis-dependent mechanism mediated by EphA receptor and vascular endothelial growth factor in mice. Cancer Res. 2006 Nov 11/1/2006; 66(21): 10315-24. PMID: 17079451, PII: 66/21/10315, DOI: 10.1158/0008-5472.CAN-06-1560, ISSN: 0008-5472.

Tang T, Shi Y, Opalenik SR, Brantley-Sieders DM, Chen J, Davidson JM, Brandt SJ. Expression of the TAL1/SCL transcription factor in physiological and pathological vascular processes. J. Pathol. 2006 Sep; 210(1): 121-9. PMID: 16841371, DOI: 10.1002/path.2028, ISSN: 0022-3417.

Hunter SG, Zhuang G, Brantley-Sieders D, Swat W, Cowan CW, Chen J. Essential role of Vav family guanine nucleotide exchange factors in EphA receptor-mediated angiogenesis. Mol. Cell. Biol. 2006 Jul; 26(13): 4830-42. PMID: 16782872, PMCID: PMC1489141, PII: 26/13/4830, DOI: 10.1128/MCB.02215-05, ISSN: 0270-7306.

Chen J, Hicks D, Brantley-Sieders D, Cheng N, McCollum GW, Qi-Werdich X, Penn J. Inhibition of retinal neovascularization by soluble EphA2 receptor. Exp. Eye Res [print-electronic]. 2006 Apr; 82(4): 664-73. PMID: 16359662, PII: S0014-4835(05)00293-9, DOI: 10.1016/j.exer.2005.09.004, ISSN: 0014-4835.

Fang WB, Brantley-Sieders DM, Parker MA, Reith AD, Chen J. A kinase-dependent role for EphA2 receptor in promoting tumor growth and metastasis. Oncogene. 2005 Nov 11/24/2005; 24(53): 7859-68. PMID: 16103880, PII: 1208937, DOI: 10.1038/sj.onc.1208937, ISSN: 0950-9232.

Brantley-Sieders DM, Fang WB, Hicks DJ, Zhuang G, Shyr Y, Chen J. Impaired tumor microenvironment in EphA2-deficient mice inhibits tumor angiogenesis and metastatic progression. FASEB J [print-electronic]. 2005 Nov; 19(13): 1884-6. PMID: 16166198, PII: 05-4038fje, DOI: 10.1096/fj.05-4038fje, ISSN: 1530-6860.

Brantley-Sieders DM, Caughron J, Hicks D, Pozzi A, Ruiz JC, Chen J. EphA2 receptor tyrosine kinase regulates endothelial cell migration and vascular assembly through phosphoinositide 3-kinase-mediated Rac1 GTPase activation. J. Cell. Sci [print-electronic]. 2004 Apr 4/15/2004; 117(Pt 10): 2037-49. PMID: 15054110, PII: jcs.01061, DOI: 10.1242/jcs.01061, ISSN: 0021-9533.

Schneider C, Strayhorn WD, Brantley DM, Nanney LB, Yull FE, Brash AR. Upregulation of 8-lipoxygenase in the dermatitis of IkappaB-alpha-deficient mice. J. Invest. Dermatol. 2004 Mar; 122(3): 691-8. PMID: 15086555, PII: JID22329, DOI: 10.1111/j.0022-202X.2004.22329.x, ISSN: 0022-202X.

Brantley-Sieders D, Schmidt S, Parker M, Chen J. Eph receptor tyrosine kinases in tumor and tumor microenvironment. Curr. Pharm. Des. 2004; 10(27): 3431-42. PMID: 15544526, ISSN: 1381-6128.

Brantley-Sieders DM, Chen J. Eph receptor tyrosine kinases in angiogenesis: from development to disease. Angiogenesis. 2004; 7(1): 17-28. PMID: 15302992, PII: 5272546, DOI: 10.1023/B:AGEN.0000037340.33788.87, ISSN: 0969-6970.

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.

Cheng N, Brantley DM, Liu H, Lin Q, Enriquez M, Gale N, Yancopoulos G, Cerretti DP, Daniel TO, Chen J. Blockade of EphA receptor tyrosine kinase activation inhibits vascular endothelial cell growth factor-induced angiogenesis. Mol. Cancer Res. 2002 Nov; 1(1): 2-11. PMID: 12496364, ISSN: 1541-7786.

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.

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.

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.

Cheng N, Brantley DM, Chen J. The ephrins and Eph receptors in angiogenesis. Cytokine Growth Factor Rev. 2002 Feb; 13(1): 75-85. PMID: 11750881, PII: S1359610101000314, ISSN: 1359-6101.

Bushdid PB, Chen CL, Brantley DM, Yull F, Raghow R, Kerr LD, Barnett JV. NF-kappaB mediates FGF signal regulation of msx-1 expression. Dev. Biol. 2001 Sep 9/1/2001; 237(1): 107-15. PMID: 11518509, PII: S0012-1606(01)90356-2, DOI: 10.1006/dbio.2001.0356, ISSN: 0012-1606.

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.

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.

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.

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.

Bushdid PB, Brantley DM, Yull FE, Blaeuer GL, Hoffman LH, Niswander L, Kerr LD. Inhibition of NF-kappaB activity results in disruption of the apical ectodermal ridge and aberrant limb morphogenesis. Nature. 1998 Apr 4/9/1998; 392(6676): 615-8. PMID: 9560159, DOI: 10.1038/33435, ISSN: 0028-0836.

Dana M Brantley. Apolipoprotein E synthesis by transplanted bone marrow derived cells in apolipoprotein E deficient mice. BIOS. 1996; 67: 74-82.