Jensen Lab Research:

My research has been focused on the breast cancer susceptibility gene 1 (BRCA1) and breast cancer for over 20 years.  I was part of the team to provide the first direct evidence that BRCA1 was a tumor suppressor.  Currently our lab has several projects aimed at understanding BRCA1 regulation and how we might leverage the tumor suppressor functions of BRCA1 therapeutically.

1. Characterization of BRCA1 as a tumor suppressor. My laboratory in conjunction with the laboratory of Dr. Jeffrey Holt published a number of seminal papers characterizing the BRCA1 protein and provided the first direct in vitro and in vivo evidence that BRCA1 functions as a tumor suppressor. In addition, our laboratories demonstrated that abnormalities in BRCA1 are not limited to cases involving germline mutation of BRCA1, and that as many as 20 to 30% of sporadic breast cancers show decreased expression of BRCA1. In retrospect, it is clear that this fraction of sporadic breast cancers corresponded to the molecular subcategory of tumors now known as triple negative breast cancer. Our 1995 paper published in Nature Genetics thus represents one of the first molecular characterizations of this critically important type of breast cancer. 
   1. Thompson ME, Jensen RA, Obermiller PS, Page DL, Holt JT. Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression. Nat Genet. 1995;9(4):444-50. PMID: 7795653.
   2. Holt JT, Thompson ME, Szabo C, Robinson-Benion C, Arteaga CL, King MC, Jensen RA. Growth retardation and tumour inhibition by BRCA1. Nat Genet. 1996;12(3):298-302. PMID: 8589721.
   3. Hoshino A, Yee CJ, Campbell M, Woltjer RL, Townsend RL, van der Meer R, Shyr Y, Holt JT, Moses HL, Jensen RA. Effects of BRCA1 transgene expression on murine mammary gland development and mutagen-induced mammary neoplasia. Int J Biol Sci. 2007;3(5):281-91. PMC1865089. 
2. Characterization of BRCA1 as a multifunctional protein. Following the discovery that BRCA1 was critically important in the homologous recombination DNA repair pathway, it is been determined that BRCA1 participates in a wide variety of critical cellular functions. My laboratory has made a number of discoveries regarding new functions of BRCA1. In conjunction with the laboratory of Edison Liu we determined that the growth arrest observed following expression of BRCA1 is critically dependent upon the presence of the retinoblastoma protein. We also demonstrated that BRCA1 binds the retinoblastoma protein and that this is critical for the growth arrest function of BRCA1.
   
   In addition, my laboratory in conjunction with Jeffrey Holt’s laboratory demonstrated that restoration of BRCA1 expression in BRCA1 defective tumor cells is capable of fully restoring the DNA repair capability that is inherently absent in cells with mutated BRCA1. Subsequently it has been shown by a number of investigators that BRCA1 function can be restored following a second mutation in BRCA1 and that this mediates a restoration of DNA repair capability in tumors. This phenomenon has been most commonly observed in ovarian cancer and our 2012 publication in PNAS demonstrated that HSP 90 inhibitors can block expression of BRCA1 and eliminate the tumor's ability to repair DNA. We also demonstrated that BRCA1 is an HSP 90 client protein. This finding suggests that platinum resistance in ovarian cancers can be overcome by treatment with HSP 90 inhibitors. If this proves to be correct, this would represent a critically important therapeutic advance. Finally, recent work in our laboratory has demonstrated that BRCA1 is an important regulatory molecule that controls the expression of numerous microRNAs. In our 2014 Oncogene paper we specifically demonstrated that BRCA1 controls the expression of epidermal growth factor receptor through transcriptional regulation of microRNA-146 a. This work helps to explain the longstanding observation that epidermal growth factor receptor is frequently overexpressed in triple negative breast cancers that lack expression of BRCA1 and suggests a molecular mechanism by which triple negative breast cancers might be targeted.

1. Aprelikova ON, Fang BS, Meissner EG, Cotter S, Campbell M, Kuthiala A, Bessho M, Jensen RA, Liu ET. BRCA1-associated growth arrest is RB-dependent. Proceedings of the National Academy of Sciences of the United States of America. 1999;96(21):11866-71. PMC18378.
2. Abbott DW, Thompson ME, Robinson-Benion C, Tomlinson G, Jensen RA, Holt JT. BRCA1 expression restores radiation resistance in BRCA1-defective cancer cells through enhancement of transcription-coupled DNA repair. J Biol Chem. 1999;274(26):18808-12. PMID: 10373498.
3. Stecklein SR, Kumaraswamy E, Behbod F, Wang W, Chaguturu V, Harlan-Williams LM, Jensen RA. BRCA1 and HSP90 cooperate in homologous and non-homologous DNA double-strand-break repair and G2/M checkpoint activation. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(34):13650-5. PMC3427093.
4. Kumaraswamy E, Wendt KL, Augustine LA, Stecklein SR, Sibala EC, Li D, Gunewardena S, Jensen RA. BRCA1 regulation of epidermal growth factor receptor (EGFR) expression in human breast cancer cells involves microRNA-146a and is critical for its tumor suppressor function. Oncogene. 2015 Aug 13;34(33):4333-46. PMC4739738