Department of Molecular Medicine
 

Rong Li Rong  LiPh.D.

Professor


Profile and Contact Information | Research | Laboratory


RESEARCH

 

Research Program

Our laboratory addresses the following three fundamental questions concerning breast cancer treatment and prevention.

1. How does BRCA1 suppress tumor development in a gender- and tissue-specific manner?
Women who carry cancer-predisposing germ-line mutations in BRCA1 have significantly increased chance of developing breast and ovarian cancers. While the BRCA1 activity in DNA repair is clearly important to the etiology of BRCA1-associated cancers, it is not clear whether the DNA repair function alone is sufficient to account for the gender- and tissue-specific tumor suppression by BRCA1. We previously identified a BRCA1-binding protein COBRA1, which is identical to the B subunit of NELF involved in pausing of RNA polymerase II. Using mouse genetics and clinical samples from BRCA1 mutation carriers, we are investigating whether a crosstalk between BRCA1 and COBRA1-regulated transcription machinery contributes to the tissue-specific function of BRCA1 in breast epithelium.

2. How can the antitumor activity of estrogen receptor β(ER β) be mobilized?
In contrast to the tumor-promoting activity of ERβ, ERβ inhibits tumor growth in breast cancer. Because ERβ is present in a significant percentage of breast cancer cases, rallying its antitumor activity could serve as a potential therapeutic approach. Our pioneer discovery of a phosphotyrosine switch for the antitumor activity of ERβ enables us to mobilize ERβ function with unprecedented precision. We are testing the hypothesis that turning on this molecular switch of ERβ can inhibit triple negative breast cancer and circumvent hormonal resistance of ERβ-positive breast cancer, two clinically pressing areas where therapeutic potential of ERβ has been previously demonstrated.

3. How do adipose stromal cells (ASC) promote breast cancer progression?
ASC is a major constituent of the breast and a source of tumor-promoting factors including estrogens. We recently discovered a new mechano-transducing pathway that links mechanical phenotype with the endocrine/paracrine output of ASCs. This pathway is initiated by a cell surface receptor called discoidin domain receptor 1 (DDR1). Combining three-dimension cell culture systems and animal models, we are exploring novel therapeutic approaches to disrupt this stroma-tumor communication.

 

Selected Publications

  1. Yuan B, Cheng L, Chiang H-C, Xu X, Han Y, Su H, Wang L, Zhang B, Li J, Tekmal J, Li X, Xie X, Wang T, Tekmal RR, Curiel TJ, Yuan Z-Y, Elledge R, Hu Y, Ye Q, Li R. (2014) A phosphotyrosine switch determines the antitumor activity of ERβ. J. Clin. Invest. 124:3378.
  2. Pan H, Qin K, Guo Z, Ma Y, April C, Gao X, Andrews TG, Bokov A, Zhang J, Chen Y, Weintraub ST, Fan J-B, Wang D, Hu Y, Aune GJ, Lindsey ML, Li R. (2014) Negative elongation factor controls energy homeostasis in cardiomyocytes. Cell Rep, 7:79.
  3. Hsu P-Y, Hsu H-K, Lan X, Juan L, Yan PS, Labanowska J, Heerema N, Hsiao T-H, Chiu Y-C, Chen Y, Liu Y, Li L, Li R, Thompson IM, Nephew KP, Sharp ZD, Kirma NB, Jin VX, Huang T H-M.(2013) Amplification of distant estrogen response elements deregulates target genes associated with tamoxifen resistance in breast cancer. Cancer Cell 24:197.
  4. Ghosh S, Ashcraft K, Jahid MJ, April C, Ghajar CM, Ruan J, Wang H, Foster M, Hughes DC, Ramirez AG, Huang T, Fan JB, Hu Y, and Li R. (2013) Regulation of adipose oestrogen output by mechanical stress. Nat Commun. 4: 1821.
  5. Sun J, Pan H, Lei C, Yuan B, Nair SJ, April C, Parameswaran B, Klotzle B, Fan JB, Ruan J, and Li R. (2011) Genetic and genomic analyses of an RNA polymerase II-pausing factor in regulation of mammalian transcription and cell growth. J Biol Chem. 286(42): 36248-57.
  6. Sun J and Li R. (2010) Human negative elongation factor activates transcription and regulates alternative transcription initiation. J Biol Chem
  7. Walter M, Liang S, Ghosh S, Hornsby PJ, and Li R. (2009) Interleukin 6 secreted from adipose stromal cells promotes migration and invasion of breast cancer cells. Oncogene. 28(30): 2745-55.
  8. Ghosh S, Choudary A, Ghosh S, Musi N, Hu Y, and Li R. (2009) IKK{beta} mediates cell shape-induced aromatase expression and estrogen biosynthesis in adipose stromal cells. Mol Endocrinol. 23(5): 662-70.
  9. Aiyar SE, Blair AL, Hopkinson DA, Bekiranov S, and Li R. (2007) Regulation of clustered gene expression by cofactor of BRCA1 (COBRA1) in breast cancer cells. Oncogene. 26(18):
  10. Hu Y, Ghosh S, Amleh A, Yue W, Lu Y, Katz A, and Li R. (2005) Modulation of aromatase expression by BRCA1: a possible link to tissue-specific tumor suppression. Oncogene. 24(56): 8343-8.
  11. Aiyar SE, Sun JL, Blair AL, Moskaluk CA, Lu YZ, Ye QN, Yamaguchi Y, Mukherjee A, Ren DM, Handa H, and Li R. (2004) Attenuation of estrogen receptor alpha-mediated transcription through estrogen-stimulated recruitment of a negative elongation factor. Genes Dev.
  12. Hu YF and Li R. (2002) JunB potentiates function of BRCA1 activation domain 1(AD1) through a coiled-coil-mediated interaction. Genes Dev. 16(12): 1509-17
  13. Ye Q, Hu YF, Zhong H, Nye AC, Belmont AS, and Li R. (2001) BRCA1-induced large-scale chromatin unfolding and allele-specific effects of cancer-predisposing mutations. J Cell Biol. 155(6): 911-21.
  14. Hu YF, Hao ZL, and Li R. (1999) Chromatin remodeling and activation of chromosomal DNA replication by an acidic transcriptional activation domain from BRCA1. Genes Dev. 13(6): 637-42.
  15. Yuan Y, Cheng L, Chiang H-C, Xu X, Han Y, Su H, Wang L, Zhang B, Lin J, Li X, Xie X, Tekmal J, Curiel TJ, Yuan Z-Y, Elledge R, Hu Y, Ye Q, Li R. (2014) A phosphotyrosine switch determines the antitumor activity of ERb. J. Clin. Invest. in press.
  16. Pan H1, Qin K1, Guo Z2, Ma Y3, April C4, Gao X5, Andrews TG6, Bokov A7, Zhang J3, Chen Y2, Weintraub ST5, Fan JB4, Wang D2, Hu Y1, Aune GJ8, Lindsey ML9, Li R10. Cell Rep. 2014 Apr 10;7(1):79-85. doi: 10.1016/j.celrep.2014.02.028. Epub 2014 Mar 20. Negative elongation factor controls energy homeostasis in cardiomyocytes.
  17. Ghosh S1, Hughes D, Parma DL, Ramirez A, Li R: Mol Biol Rep. 2014 Jan 24. [Epub ahead of print] Association of obesity and circulating adipose stromal cells among breast cancer survivors.
  18. Pei-Yin Hsu, Hang-Kai Hsu, Xun Lan, Liran Juan, Pearlly S. Yan, Jadwiga Labanowska, Nyla Heerema, Tzu-Hung Hsiao, Yu-Chiao Chiu, Yidong Chen, Yunlong Liu, Lang Li, Rong Li, Ian M. Thompson, Kenneth P. Nephew, Zelton D. Sharp, Nameer B. Kirma, Victor X. Jin, Tim H.-M. Huang Amplification of Distant Estrogen Response Elements Deregulates Target Genes Associated with Tamoxifen Resistance in Breast Cancer
  19. Ghosh S, Ashcraft K, Jahid MJ, April C, Ghajar CM, Ruan J, Wang H, Foster M, Hughes DC, Ramirez AG, Huang T, Fan JB, Hu Y, and Li R: (2013) Regulation of adipose oestrogen output by mechanical stress. Nat Commun. 4: 1821.
  20. Chiang HC, Nair SJ, Yeh IT, Santillan AA, Hu Y, Elledge R, and Li R: (2012) Assocation of radiotherapy with preferential depletion of luminal epithelial cells in a BRCA1 mutation carrier. Exp Hematol Oncol. 1(1): 31.
  21. Sun J, Pan H, Lei C, Yuan B, Nair SJ, April C, Parameswaran B, Klotzle B, Fan JB, Ruan J, and Li R: (2011) Genetic and genomic analyses of an RNA polymerase II-pausing factor in regulation of mammalian transcription and cell growth. J Biol Chem. 286(42): 36248-57.
  22. Ghosh S, Kang T, Wang H, Hu Y, and Li R: (2011) Mechanical phenotype is important for stromal aromatase expression. Steroids. 76(8): 797-801.
  23. Vachon CM, Sasano H, Ghosh K, Brandt KR, Watson DA, Reynolds C, Lingle WL, Goss PE, Li R Aiyar SE, Scott CG, Pankratz VS, Santen RJ, and Ingle JN: (2011) Aromatase immunoreactivity is increased in mammographically dense regions of the breast. Breast Cancer Res Treat. 125(1): 243-52.
  24. Ghosh S, Dean A, Walter M, Bao Y, Hu Y, Ruan J, and Li R: (2010) Cell density-dependent transcriptional activation of endocrine-related genes in human adipose tissue-derived stem cells. Exp Cell Res. 316(13): 2087-98.
  25. Sun J and Li R: (2010) Human negative elongation factor activates transcription and regulates alternative transcription initiation. J Biol Chem. 285(9): 6443-52.
  26. Ghosh S, Hu Y, and LI R: (2010) Cell density is a critical determinant of aromatase expression in adipose stromal cells. J Steroid Biochem Mol Biol. 118(4-5): 231-6.
  27. Wang H, Li R, and Hu Y: (2009) The alternative noncoding exons 1 of aromatase (cyp19) gene modulate gene expression in a posttranscriptional manner. Endocrinology. 150(7): 3301-7.
  28. Walter M, Liang S, Ghosh S, Hornsby PJ, and Li R: (2009) Interleukin 6 secreted from adipose stromal cells promotes migration and invasion of breast cancer cells. Oncogene. 28(30): 2745-55.
  29. Ghosh S, Choudary A, Ghosh S, Musi N, Hu Y, and Li R: (2009) IKK{beta} mediates cell shape-induced aromatase expression and estrogen biosynthesis in adipose stromal cells. Mol Endocrinol. 23(5): 662-70.
  30. Amleh A, Nair SJ, Sun J, Sutherland A, Hasty P, and Li R: (2009) Mouse cofactor of BRCA1 (Cobra1) is required for early embryogenesis. PLoS ONE. 4(4): e5034.
  31. Wen J, Li R, Lu Y, and Shupnik, MA: (2009) Decreased BRCA1 confers tamoxifen resistance in breast cancer cells by altering estrogen receptor-coregulator interactions. Oncogene. 28(4): 575-86.
  32. Kang HJ, Kim HJ, Cho CH, Hu Y, Li R, and Bae I: (2008) BRCA1 transcriptional activity is enhanced by interactions between its AD1 domain and AhR. Cancer Chemother Pharmacol. 62(6): 965-75.
  33. Sun J, Watkins G, Blair AL, Moskaluk C, Ghosh S, Jiang WG, and Li R: (2008) Deregulation of cofactor of BRCA1 expression in breast cancer cells. J Cell Biochem. 103(6): 1798-807.
  34. Aiyar SE, Cho H, Lee J, and Li R: (2007) Concerted transcriptional regulation by BRCA1 and COBRA1 in breast cancer cells. Int J Biol Sci. 3(7): 486-92.
  35. Sun J, Blair AL, Aiyar SE, and Li R: (2007) Cofactor of BRCA1 modulates androgen-dependent transcription and alternative splicing. J Steroid Biochem Mol Biol. 107(3-5): 131-9.
  36. Aiyar SE, Blair AL, Hopkinson DA, Bekiranov S, and Li R: (2007) Regulation of clustered gene expression by cofactor of BRCA1 (COBRA1) in breast cancer cells. Oncogene. 26(18): 2543-53.
  37. Lu Y, Amleh A, Sun J, Jin X, McCullough SD, Baer R, Ren D, Li R*, and Hu Y* (*co-corresponding authors): (2007) Ubiquitination and proteasome-mediated degradation of BRCA1 and BARD1 during steroidogenesis in human ovarian granulosa cells. Mol Endocrinol. 21(3): 651-63.
  38. Ghosh S, Lu Y, Katz A, Hu Y, and Li R: (2007) Tumor suppressor BRCA1 inhibits a breast cancer-associated promoter of the aromatase gene (CYP19) in human adipose stromal cells. Am J Physiol Endocrinol Metab. 292(1): E246-52.
  39. McChesney PA, Aiyar SE, Lee OJ, Zaika A, Moskaluk C, Li R, and El-Rifai W: (2006) Cofactor of BRCA1: a novel transcription factor regulator in upper gastrointestinal carcinomas. Cancer Res. 66(3): 1346-53.
  40. Hu Y, Ghosh S, Amleh A, Yue W, Lu Y, Katz A, and Li R: (2005) Modulation of aromatase expression by BRCA1: a possible link to tissue-specific tumor suppression. Oncogene. 24(56): 8343-8.
  41. Wu Y, Lu Y, Hu Y, and Li R: (2005) Cyclic AMP-dependent modification of gonad-selective TAF(II)105 in a human ovarian granulosa cell line. J Cell Biochem. 96(4): 751-9.
  42. Aiyar S, Sun JL, and Li R: (2005) BRCA1: a locus-specific “liaison” in gene expression and genetic integrity. J Cell Biochem. 94(6): 1103-11.
  43. Ghosh S, Wu Y, Li R*, and Hu Y* (*co-corresponding authors): (2005) Jun proteins modulate the ovary-specific promoter of aromatase gene in ovarian granulosa cells via a cAMP-responsive element. Oncogene. 24(13): 2236-46.
  44. Loch CM, Mosammaparast N, Miyake T, Pemberton LF and Li R: (2004) Functional and physical interactions between autonomously replicating sequence-binding factor 1 and the nuclear transport machinery. Traffic. 5(12): 925-35.
  45. Yarragudi A, Miyake T, Li R, and Morse RH: (2004) Comparison of ABF1 and RAP1 in chromatin opening and transactivator potentiation in the budding yeast Saccharomyces cerevisiae. Mol Cell Biol. 24(20): 9152-64.
  46. Aiyar SE, Sun JL, Blair AL, Moskaluk CA, Lu YZ, Ye QN, Yamaguchi Y, Mukherjee A, Ren DM, Handa H, and Li R: (2004) Attenuation of estrogen receptor alpha-mediated transcription through estrogen-stimulated recruitment of a negative elongation factor. Genes Dev. 18(17): 2134-46.
  47. Miyake T, Reese J, Loch CM, Auble DT, and Li R: (2004) Genome-wide analysis of ARS (autonomously replicating sequence) binding factor 1 (Abf1p)-mediated transcriptional regulation in Saccharomyces cerevisiae. J Biol Chem. 279(33): 34865-72.
  48. Fourel G, Miyake T, Defossez PA, Li R, and Gilson E: (2002) General regulatory factors (GRFs) as genome partitioners. J Biol Chem. 277(44): 41736-43.
  49. Hu YF and Li R: (2002) JunB potentiates function of BRCA1 activation domain 1(AD1) through a coiled-coil-mediated interaction. Genes Dev. 16(12): 1509-17.
  50. Miyake T, Loch CM, and Li R: (2002) Identification of a multifunctional domain in autonomously replicating sequence-binding factor 1 required for transcriptional activation, DNA replication, and gene silencing. Mol Cell Biol. 22(2): 505-16.
  51. Choudhary SK and Li R: (2002) BRCA1 modulates ionizing radiation-induced nuclear focus formation by the replication protein A p34 subunit. J Cell Biochem. 84(4): 666-74.
  52. Ye Q, Hu YF, Zhong H, Nye AC, Belmont AS, and Li R: (2001) BRCA1-induced large-scale chromatin unfolding and allele-specific effects of cancer-predisposing mutations. J Cell Biol. 155(6): 911-21.
  53. Hu YF, Hao ZL, and Li R: (1999) Chromatin remodeling and activation of chromosomal DNA replication by an acidic transcriptional activation domain from BRCA1. Genes Dev. 13(6): 637-42.