Profile picture for user koco223

Kathleen L. O'Connor, PhD

Connect

859-323-7534
kloconnor@uky.edu
HKRB 344

Positions

  • Professor, Molecular and Cellular Biochemistry
  • Associate Director of Cancer Education and Mentoring, Markey Cancer Center
  • Director, Markey Science Training in Research, Oncology, Networking and professional Growth (STRONG) Scholars Program
  • Director, Markey STRONG Post-baccalaureate Fellows Program

College Unit(s)

Other Affiliation(s)
  • Markey Cancer Center
  • Diversity Departmental Ambassadors
  • MD/PhD Program Mentor

Biography and Education

Education

B.S., James Madison University, 1988

Ph.D., Case Western Reserve University, 1996

Post-doctoral training, Harvard Medical School, 2001

Research

My research focuses on how integrin signaling promotes carcinoma invasion and metastasis with special emphasis on the integrin α6β4. Integrin α6β4 confers an invasive and metastatic phenotype in many types of carcinomas, including triple-receptor negative breast cancer (TNBC). Dissecting the pathways altered by integrin α6β4 has given and will continue to contribute great insight into the processes that perpetuate an invasive and metastatic phenotype. I originally discovered links between integrin signaling and the cAMP pathway (JCB, 1998; JBC, 2001), and also determined that integrin α6β4 could stimulate the small GTPase RhoA leading to lamellae formation (JCB, 2000; Oncogene 2013). We have further expanded our work to include investigations on how integrin α6β4 modifies the transcriptome toward an invasion signature. Through these studies, we have identified the first transcriptional targets for NFAT1 (Oncogene 2005) and NFAT5 (JBC 2009) in cancer and found that integrin α6β4 can stimulate select demethylation of the promoters of pro-metastatic genes, including S100A4/metastasin (JBC 2009), amphiregulin and epiregulin (JBC 2015). Our work on how integrin α6β4 mediates promoter DNA demethylation uncovered a novel function for the integrin in regulating DNA repair. We find that the integrin stimulates and utilizes base excision repair in active DNA demethylation. We also found that the ability to stimulate DNA repair extends also to nucleotide excision repair (Sci Rep 2017) and non-homologous end joining (BioRxiv, 2019). Our overarching long-term goal is to determine how integrin α6β4 drives the aggressive properties of TNBC so that this information can be used to guide precision medicine for TNBC.

Selected Publications

  1. Chen M, Marrs B, Qi L, Knifley T, Weiss HL, D’Orazio JA, and O’Connor KL. Integrin α6β4 signals through DNA damage response pathway to sensitize breast cancer cells to cisplatin. Front. Oncol. 12:1043538. 2022.  doi: 10.3389/fonc.2022.1043538
  2. Qi L, Chen M, Knifley T, and O’Connor KL. Integrin α6β4 requires plectin binding and vimentin to drive adhesion complex distribution and invasive growth. Journal of Cell Science, 15;135(2):jcs258471, 2022. PMCID: PMC8917354. PMID: 34897465.
  3. Qi L, Knifley T, Piecoro DW, Rychahou P, Wu J, O’Connor KL, Chen M. Spontaneous Metastasis Assays Using A549 Lung Cancer Cells. Bio-protocol. 2020 April; 10(7):3579. doi: 10.21769/BioProtoc.3579.
  4. O'Connor KL. Building a Cancer Education Program in the Modern Era: Lessons from Stone Soup. J Cancer Educ. 2020 Feb;35(1):205-209. doi: 10.1007/s13187-019-01514-5. PubMed PMID: 30887313; PubMed Central PMCID: PMC6751031.
  5. Huang X, Ye Q, Chen M, Li A, Mi W, Fang Y, Zaytseva YY, O'Connor KL, Vander Kooi CW, Liu S, She QB. N-glycosylation-defective splice variants of neuropilin-1 promote metastasis by activating endosomal signals. Nat Commun. 2019 Aug 16;10(1):3708. doi: 10.1038/s41467-019-11580-4. PubMed PMID: 31420553; PubMed Central PMCID: PMC6697747.
  6. Harper NW, Hodges KB, Stewart RL, Wu J, Huang B, O'Connor KL, Romond EH. Adjuvant Treatment of Triple-Negative Metaplastic Breast Cancer With Weekly Paclitaxel and Platinum Chemotherapy: Retrospective Case Review From a Single Institution. Clin Breast Cancer. 2019 Aug;19(4):e495-e500. doi: 10.1016/j.clbc.2019.05.009. Epub 2019 May 24. PubMed PMID: 31208874; PubMed Central PMCID: PMC6693323.
  7. Liu L, Qi L, Knifley T, Piecoro DW, Rychahou P, Liu J, Mitov MI, Martin J, Wang C, Wu J, Weiss HL, Butterfield DA, Evers BM, O'Connor KL, Chen M.S100A4 alters metabolism and promotes invasion of lung cancer cells by up-regulating mitochondrial complex I protein NDUFS2. J Biol Chem.2019 May 3;294(18):7516-7527. doi: 10.1074/jbc.RA118.004365. Epub 2019 Mar 18. PubMed PMID: 30885944; PubMed Central PMCID: PMC6509482.
  8. Xiong G, Stewart RL, Chen J, Gao T, Scott TL, Samayoa LM, O'Connor K, Lane AN, Xu R. Collagen prolyl 4-hydroxylase 1 is essential for HIF-1α stabilization and TNBC chemoresistance. Nat Commun. 2018 Oct 26;9(1):4456. doi: 10.1038/s41467-018-06893-9. PubMed PMID: 30367042; PubMed Central PMCID: PMC6203834.
  9. Carpenter BL, Liu J, Qi L, Wang C, O'Connor KL. Integrin α6β4 Upregulates Amphiregulin and Epiregulin through Base Excision Repair-Mediated DNA Demethylation and Promotes Genome-wide DNA Hypomethylation. Sci Rep. 2017 Jul 21;7(1):6174. doi: 10.1038/s41598-017-06351-4. PubMed PMID: 28733611; PubMed Central PMCID: PMC5522472.

  10. Stewart RL, O'Connor KL. Integrin β4 is a controversial target for non-small cell lung cancer-reply. Hum Pathol. 2017 Mar;61:223-224. doi: 10.1016/j.humpath.2016.09.032. Epub 2016 Nov 2. PubMed PMID: 27816722.

  11. Stewart RL, West D, Wang C, Weiss HL, Gal T, Durbin EB, O'Connor W, Chen M, O'Connor KL. Elevated integrin α6β4 expression is associated with venous invasion and decreased overall survival in non-small cell lung cancer. Hum Pathol. 2016 Aug;54:174-83. doi: 10.1016/j.humpath.2016.04.003. Epub 2016 Apr 20. PubMed PMID: 27107458; PubMed Central PMCID: PMC4938774.

    Cited in PMC

  12. Stewart RL, Carpenter BL, West DS, Knifley T, Liu L, Wang C, Weiss HL, Gal TS, Durbin EB, Arnold SM, O'Connor KL, Chen M. S100A4 drives non-small cell lung cancer invasion, associates with poor prognosis, and is effectively targeted by the FDA-approved anti-helminthic agent niclosamide. Oncotarget. 2016 Jun 7;7(23):34630-42. doi: 10.18632/oncotarget.8969. PubMed PMID: 27127879; PubMed Central PMCID: PMC5085181.

    Free full text    Cited in PMC

  13. Carpenter BL, Chen M, Knifley T, Davis KA, Harrison SM, Stewart RL, O'Connor KL. Integrin α6β4 Promotes Autocrine Epidermal Growth Factor Receptor (EGFR) Signaling to Stimulate Migration and Invasion toward Hepatocyte Growth Factor (HGF). J Biol Chem. 2015 Nov 6;290(45):27228-38. doi: 10.1074/jbc.M115.686873. Epub 2015 Sep 17. PubMed PMID: 26381405; PubMed Central PMCID: PMC4646402.

    Free full text    Cited in PMC

  14. Stewart RL, O'Connor KL. Clinical significance of the integrin α6β4 in human malignancies. Lab Invest. 2015 Sep;95(9):976-86. doi: 10.1038/labinvest.2015.82. Epub 2015 Jun 29. Review. PubMed PMID: 26121317; PubMed Central PMCID: PMC4554527.

    Free full text   Cited in PMC

  15. Zaytseva YY, Elliott VA, Rychahou P, Mustain WC, Kim JT, Valentino J, Gao T, O'Connor KL, Neltner JM, Lee EY, Weiss HL, Evers BM. Cancer cell-associated fatty acid synthase activates endothelial cells and promotes angiogenesis in colorectal cancer.Carcinogenesis. 2014 Jun;35(6):1341-51. doi: 10.1093/carcin/bgu042. Epub 2014 Feb 7. PubMed PMID: 24510238; PubMed Central PMCID: PMC4043242.

    Free full text   Cited in PMC

  16. Yin Y, Deng X, Liu Z, Baldwin LA, Lefringhouse J, Zhang J, Hoff JT, Erfani SF, Rucker EB 3rd, O'Connor K, Liu C, Wu Y, Zhou BP, Yang XH. CD151 represses mammary gland development by maintaining the niches of progenitor cells. Cell Cycle. 2014;13(17):2707-22. doi: 10.4161/15384101.2015.945823. PubMed PMID: 25486358; PubMed Central PMCID: PMC4614859.

    Free full text    Cited in PMC

  17. Chen M, Knifley T, Subramanian T, Spielmann HP, O'Connor KL. Use of synthetic isoprenoids to target protein prenylation and Rho GTPases in breast cancer invasion. PLoS One. 2014 Feb 26;9(2):e89892. doi: 10.1371/journal.pone.0089892. eCollection 2014. PubMed PMID: 24587105; PubMed Central PMCID: PMC3935959.

    Free full text    Cited in PMC

  18. Harrison SM, Knifley T, Chen M, O'Connor KL. LPA, HGF, and EGF utilize distinct combinations of signaling pathways to promote migration and invasion of MDA-MB-231 breast carcinoma cells. BMC Cancer. 2013 Oct 27;13:501. doi: 10.1186/1471-2407-13-501. PubMed PMID: 24160245; PubMed Central PMCID: PMC3819718.

    Free full text    Cited in PMC

  19. Chen M, Bresnick AR, O'Connor KL. Coupling S100A4 to Rhotekin alters Rho signaling output in breast cancer cells. Oncogene. 2013 Aug 8;32(32):3754-64. doi: 10.1038/onc.2012.383. Epub 2012 Sep 10. PubMed PMID: 22964635; PubMed Central PMCID: PMC3525797.

    Free full text    Cited in PMC

  20. O'Connor K, Chen M. Dynamic functions of RhoA in tumor cell migration and invasion. Small GTPases. 2013 Jul-Sep;4(3):141-7. doi: 10.4161/sgtp.25131. Epub 2013 Jun 10. Review. PubMed PMID: 24025634; PubMed Central PMCID: PMC3976970.

    Free full text    Cited in PMC

  21. Lee S, Qiao J, Paul P, O'Connor KL, Evers MB, Chung DH. FAK is a critical regulator of neuroblastoma liver metastasis.Oncotarget. 2012 Dec;3(12):1576-87. PubMed PMID: 23211542; PubMed Central PMCID: PMC3681496.

    Free full text    Cited in PMC

  22. Zaytseva YY, Rychahou PG, Gulhati P, Elliott VA, Mustain WC, O'Connor K, Morris AJ, Sunkara M, Weiss HL, Lee EY, Evers BM. Inhibition of fatty acid synthase attenuates CD44-associated signaling and reduces metastasis in colorectal cancer. Cancer Res. 2012 Mar 15;72(6):1504-17. doi: 10.1158/0008-5472.CAN-11-4057. Epub 2012 Jan 19. PubMed PMID: 22266115; PubMed Central PMCID: PMC3596828.

    Free full text    Cited in PMC

  23. O'Connor KL, Chen M, Towers LN. Integrin α6β4 cooperates with LPA signaling to stimulate Rac through AKAP-Lbc-mediated RhoA activation. Am J Physiol Cell Physiol. 2012 Feb 1;302(3):C605-14. doi: 10.1152/ajpcell.00095.2011. Epub 2011 Nov 2. PubMed PMID: 22049212; PubMed Central PMCID: PMC3287157.

    Free full text    Cited in PMC

  24. Chen M, Sastry SK, O'Connor KL. Src kinase pathway is involved in NFAT5-mediated S100A4 induction by hyperosmotic stress in colon cancer cells. Am J Physiol Cell Physiol. 2011 May;300(5):C1155-63. doi: 10.1152/ajpcell.00407.2010. Epub 2011 Feb 2. PubMed PMID: 21289293.

    Cited in PMC

  25. Gulhati P, Bowen KA, Liu J, Stevens PD, Rychahou PG, Chen M, Lee EY, Weiss HL, O'Connor KL, Gao T, Evers BM. mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways. Cancer Res. 2011 May 1;71(9):3246-56. doi: 10.1158/0008-5472.CAN-10-4058. Epub 2011 Mar 23. PubMed PMID: 21430067; PubMed Central PMCID: PMC3085654.

    Free full text    Cited in PMC

  26. Murillo CA, Woodside KJ, Guo Q, Zhang S, O'Connor KL, Hunter GC. Integrin and matrix metalloproteinase expression in human carotid plaque. J Surg Res. 2009 Jul;155(1):157-64. doi: 10.1016/j.jss.2008.08.005. Epub 2008 Sep 7. PubMed PMID: 19394653.

    Cited in PMC

  27. Paulucci-Holthauzen AA, Vergara LA, Bellot LJ, Canton D, Scott JD, O'Connor KL. Spatial distribution of protein kinase A activity during cell migration is mediated by A-kinase anchoring protein AKAP Lbc. J Biol Chem. 2009 Feb 27;284(9):5956-67. doi: 10.1074/jbc.M805606200. Epub 2008 Dec 23. PubMed PMID: 19106088; PubMed Central PMCID: PMC2645839.

    Free full text    Cited in PMC

  28. Chen M, Sinha M, Luxon BA, Bresnick AR, O'Connor KL. Integrin alpha6beta4 controls the expression of genes associated with cell motility, invasion, and metastasis, including S100A4/metastasin. J Biol Chem. 2009 Jan 16;284(3):1484-94. doi: 10.1074/jbc.M803997200. Epub 2008 Nov 14. PubMed PMID: 19011242; PubMed Central PMCID: PMC2615501.

    Free full text    Cited in PMC

  29. Cruz-Monserrate Z, O'Connor KL. Integrin alpha 6 beta 4 promotes migration, invasion through Tiam1 upregulation, and subsequent Rac activation. Neoplasia. 2008 May;10(5):408-17. PubMed PMID: 18472958; PubMed Central PMCID: PMC2373869.

    Free full text    Cited in PMC

  30. Cruz-Monserrate Z, Qiu S, Evers BM, O'Connor KL. Upregulation and redistribution of integrin alpha6beta4 expression occurs at an early stage in pancreatic adenocarcinoma progression. Mod Pathol. 2007 Jun;20(6):656-67. Epub 2007 Apr 13. PubMed PMID: 17415382; PubMed Central PMCID: PMC4697742.

    Free full text    Cited in PMC

  31. Chen M, Towers LN, O'Connor KL. LPA2 (EDG4) mediates Rho-dependent chemotaxis with lower efficacy than LPA1 (EDG2) in breast carcinoma cells. Am J Physiol Cell Physiol. 2007 May;292(5):C1927-33. PubMed PMID: 17496233.

    Cited in PMC

  32. Li J, O'Connor KL, Cheng X, Mei FC, Uchida T, Townsend CM Jr, Evers BM. Cyclic adenosine 5'-monophosphate-stimulated neurotensin secretion is mediated through Rap1 downstream of both Epac and protein kinase A signaling pathways. Mol Endocrinol. 2007 Jan;21(1):159-71. Epub 2006 Oct 26. PubMed PMID: 17068197.

    Cited in PMC

  33. Paulucci-Holthauzen AA, O'Connor KL. Use of pseudosubstrate affinity to measure active protein kinase A. Anal Biochem. 2006 Aug 15;355(2):175-82. Epub 2006 Jun 19. PubMed PMID: 16842735.

    Cited in PMC

  34. Chen M, O'Connor KL. Integrin alpha6beta4 promotes expression of autotaxin/ENPP2 autocrine motility factor in breast carcinoma cells. Oncogene. 2005 Jul 28;24(32):5125-30. PubMed PMID: 15897878.

    Cited in PMC

  35. Li J, O'Connor KL, Greeley GH Jr, Blackshear PJ, Townsend CM Jr, Evers BM. Myristoylated alanine-rich C kinase substrate-mediated neurotensin release via protein kinase C-delta downstream of the Rho/ROK pathway. J Biol Chem. 2005 Mar 4;280(9):8351-7. Epub 2004 Dec 28. PubMed PMID: 15623535.

    Cited in PMC

  36. Li J, O'Connor KL, Hellmich MR, Greeley GH Jr, Townsend CM Jr, Evers BM. The role of protein kinase D in neurotensin secretion mediated by protein kinase C-alpha/-delta and Rho/Rho kinase. J Biol Chem. 2004 Jul 2;279(27):28466-74. Epub 2004 Apr 27. PubMed PMID: 15123666.

    Cited in PMC

  37. Farrow B, Rychahou P, O'Connor KL, Evers BM. Butyrate inhibits pancreatic cancer invasion. J Gastrointest Surg. 2003 Nov;7(7):864-70. PubMed PMID: 14592659.

    Cited in PMC

  38. Farrow B, Rychahou P, Murillo C, O'connor KL, Iwamura T, Evers BM. Inhibition of pancreatic cancer cell growth and induction of apoptosis with novel therapies directed against protein kinase A. Surgery. 2003 Aug;134(2):197-205. PubMed PMID: 12947318.

    Cited in PMCRelated citations

  39. Farrow B, O'Connor KL, Hashimoto K, Iwamura T, Evers BM. Selective activation of PPARgamma inhibits pancreatic cancer invasion and decreases expression of tissue plasminogen activator. Surgery. 2003 Aug;134(2):206-12. PubMed PMID: 12947319.

    Cited in PMCRelated citations

  40. O'Connor KL, Mercurio AM. Protein kinase A regulates Rac and is required for the growth factor-stimulated migration of carcinoma cells. J Biol Chem. 2001 Dec 21;276(51):47895-900. Epub 2001 Oct 17. PubMed PMID: 11606581.

    Cited in PMC

  41. Mercurio AM, Bachelder RE, Chung J, O'Connor KL, Rabinovitz I, Shaw LM, Tani T. Integrin laminin receptors and breast carcinoma progression. J Mammary Gland Biol Neoplasia. 2001 Jul;6(3):299-309. Review. PubMed PMID: 11547899.

    Cited in PMC

  42. Mercurio AM, Bachelder RE, Rabinovitz I, O'Connor KL, Tani T, Shaw LM. The metastatic odyssey: the integrin connection. Surg Oncol Clin N Am. 2001 Apr;10(2):313-28, viii-ix. Review. PubMed PMID: 11382589.

    Cited in PMC

  43. O'Connor KL, Nguyen BK, Mercurio AM. RhoA function in lamellae formation and migration is regulated by the alpha6beta4 integrin and cAMP metabolism. J Cell Biol. 2000 Jan 24;148(2):253-8. PubMed PMID: 10648558; PubMed Central PMCID: PMC2174290.

    Free full text    Cited in PMC

  44. O'Connor KL, Shaw LM, Mercurio AM. Release of cAMP gating by the alpha6beta4 integrin stimulates lamellae formation and the chemotactic migration of invasive carcinoma cells. J Cell Biol. 1998 Dec 14;143(6):1749-60. PubMed PMID: 9852165; PubMed Central PMCID: PMC2132981.

    Free full text    Cited in PMC

  45. Culp LA, Lin W, Kleinman NR, O'Connor KL, Lechner R. Earliest steps in primary tumor formation and micrometastasis resolved with histochemical markers of gene-tagged tumor cells. J Histochem Cytochem. 1998 May;46(5):557-68. Review. PubMed PMID: 9562566.

    Cited in PMC

  46. Culp LA, O'Connor KL, Lechner R. Principles of Medical Biology, Volume 7B. Bittar E, editor. Greenwich, CT: JAI Press; 1997. Chapter 25, Extracellular matrix adhesion: Biological, molecular and pathological mechanisms; p.573-607.  

  47. O'Connor KL, Culp LA. Quantitation of two histochemical markers in the same extract using chemiluminescent substrates.Biotechniques. 1994 Sep;17(3):502-6, 508-9. PubMed PMID: 7818904.

  48. O'Connor KL, Culp LA. Topological and quantitative analyses of early events in tumor formation using histochemically-tagged transformed 3T3 cells. Oncology reports. 1994; 1:869-896.

  49. Lin WC, O'Connor KL, Culp LA. Complementation of two related tumour cell classes during experimental metastasis tagged with different histochemical marker genes. Br J Cancer. 1993 May;67(5):910-21. PubMed PMID: 8494724; PubMed Central PMCID: PMC1968424.

    Free full text    Cited in PMC

  50. Strayer DS, Jerng HH, O'Connor K. Sequence and analysis of a portion of the genomes of Shope fibroma virus and malignant rabbit fibroma virus that is important for viral replication in lymphocytes. Virology. 1991 Dec;185(2):585-95. PubMed PMID: 1660196.

    Cited in PMC

  51. Heard HK, O'Connor K, Strayer DS. Molecular analysis of immunosuppression induced by virus replication in lymphocytes. J Immunol. 1990 May 15;144(10):3992-9. PubMed PMID: 2159037.

    Cited in PMC

  52. Dendinger JE, O'Connor KL. Purification and characterization of a trypsin-like enzyme from the midgut gland of the Atlantic Blue Crab, Callinectes sapidus. Comp. Biochem. Physiol.. 1990; 95B:525-530.