Department of Molecular Medicine
 

Rong Li Rong  LiPh.D.

Professor


Profile and Contact Information | Research | Laboratory


RESEARCH

 

Research Program

A major aspect of the research in my lab is transcriptional regulation during normal mammary gland development and breast cancer development. Among the several transcriptional regulators that we are studying, Cofactor of BRCA1 (COBRA1) binds to tumor suppressor BRCA1 and exhibits a chromatin unfolding activity. We also show that COBRA1 functions as a subunit of the negative elongation protein (NELF) complex to modulate RNA polymerase II movement and transcription of estrogen-responsive genes in breast cancer cells. This represents a novel mechanism by which hormone-mediated gene expression is regulated. We are currently using molecular, cellular, and genetic approaches to examine the exact impact of COBRA1/NELF on transcription and proliferation of normal and cancer cells. In addition, we are actively exploring the functional interactions between BRCA1 and COBRA1/NELF in estrogen-dependent gene expression and genome instability during normal mammary gland development and tumor progression.

In a separate research direction, we have been investigating the impact of adipose stromal cells (ASCs) on breast cancer development. ASC is a major constituent of the breast and it produces a plethora of secreted factors including estrogens. We are currently using three-dimensional (3D) co-culture systems and xenograft mouse models to study the signal transduction pathway(s) that regulate the estrogen-producing capability of ASCs. Our recent studies have led to the discovery of a previously unappreciated mechanotransducing pathway that links mechanical phenotype with the endocrine/paracrine output of ASCs. Our results indicate that deregulation of this pathway has a significant impact on the ability of ASCs to stimulate proliferation of estrogen receptor (ER)+ breast cancer cells. By looking outside the “box” of breast tumor cells, we wish to emphasize the impact of mechanical cues on stromal-tumoral interactions. Results from our work may shed light on the molecular basis of several well-documented risk factors for breast cancer.

 

Selected Publications

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. Sun J and Li R: (2010) Human negative elongation factor activates transcription and regulates alternative transcription initiation. J Biol Chem. 285(9): 6443-52.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. 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.
  24. 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.
  25. 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.
  26. 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.
  27. 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.
  28. 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.
  29. 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.
  30. 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.
  31. 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.
  32. 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.
  33. 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.
  34. 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.
  35. 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.