Lee Lab

The main focus of the laboratory is to understand how insulin-like growth factors (IGFs) regulate breast transformation, and how this knowledge can be used for successful treatment of patients. This research involves basic studies into the mechanisms of IGF signaling including proteomic and transcriptomic analysis, and comparison to the highly related insulin receptor. The laboratory has created and/or characterized transgenic mice overexpressing most members of the IGF signaling family (IGF-I, IGF-IR, IRS1 and IRS2) and all develop mammary tumors. The lab uses knockout mice (IGF-R fl/fl, and IRS1 and IRS2 germ-line knockout) to decipher the importance of IGF signaling in initiation and progression of breast cancer. Basic studies are translated into preclinical work using anti-IGF-IR antibodies and tyrosine kinase inhibitors in transgenic and xenograft models. Finally, the Lee lab is the central lab for all tissue biomarker studies in clinical trials of the anti-IGF-IR antibody Figitumumab (Pfizer).

Dr. Lee’s lab also studies the role of novel nanotechnology agents in the imaging and treatment of early breast cancer. This includes the use of ultrashort carbon nanotubes filled with gadolinium or iron oxide as both imaging (MRI, T1 and T2) and treatment (via thermal ablation using AMF). Recent studies use silicon nanoshells containing gold and iron oxide, and then with anti-IGF-IR antibodies, for targeted imaging (IF using gold and MRI using T2 iron oxide) and therapy (via thermal ablation). Finally, the Lee laboratory uses massively parallel sequencing to perform fundamental studies on the role of structural genomic rearrangements in breast cancer.

 Lee Research Group


Below displays the Research Details from the profile of each member of the lab.

Adrian Lee, PhD

The goal of the Lee laboratory is translational breast cancer research. The laboratory has two main areas of focus.

The first involves targeting the insulin-like growth factor pathway in breast cancer. A major emphasis is upon the downstream signaling intermediates the insulin receptor substrates (IRSs) analyzing interactions with steroid hormone receptors (ER and PR), role in normal mouse mammary gland development, mechanisms of transformation of mammary epithelial cells in vitro and in mouse models, and roles in human breast cancer. These studies include a systems biology approach to understanding the pathway that includes use of transcriptomics (RNA-seq) and proteomics (Reverse Phase Protein Arrays).

The second area of research is the role of massively parallel sequencing in precision cancer genomic medicine. This work includes basic studies on mutations in breast cancer and then methods (both technical and computational) to apply this in the clinical setting. Studies examine tumor heterogeneity and molecular changes during progression, with a particular focus on DNA and RNA structural rearrangements in metastasis. Analysis includes use of long-insert mate-pair, whole genome, whole exome and RNA-sequencing which have all been completed on a set of 20 tissues to allow an unprecedented integrated view of genomic and transcriptomic changes during progression. Genomic alterations are measured in blood (circulating-free DNA) using targeted sequencing and ddPCR. Computational methods are being developed and optimized for analyzing clonal architecture, evolutionary genomic change, and refinement of structural rearrangements. The laboratory has also developed a breast cancer specific next-generation sequencing test for clinical sequencing and developing a computational architecture for integration of patient genomic and phenotypic data for research and clinical (Oracle Translational Research Center) use.

http://adrianleelab.com/

 

 


Ashuvinee Elangovan
Graduate Student Researcher


Adrian Lee, PhD
Professor; Pittsburgh Foundation Chair in Precision Medicine

Adrian Lee, PhD

Journal Articles

Li Z, Levine KM, Bahreini A, Wang P, Chu D, Park BH, Oesterreich S and Lee AV. Upregulation of IRS1 enhances IGF1 response in Y537S and D538G ESR1 mutant breast cancer cells. Endocrinology 159:285-296, 2018.
Priedigkeit N, Watters RJ, Lucas PC, Basudan A, Bhargava R, Horne W, Kolls JK, Fang Z, Rosenzweig MQ, Brufsky AM, Weiss KR, Oesterreich S and Lee AV. Exome-capture RNA sequencing of decade-old breast cancers and matched decalcified bone metastases. JCI Insight 2:e95703, 2017.
Priedigkeit N, Hartmaier RJ, Chen Y, Vareslija D, Basudan A, Watters RJ, Thomas R, Leone JP, Lucas PC,  Bhargava R, Hamilton RL, Chmielecki J, Puhalla SL, Davidson NE, Oesterreich S, Brufsky AM, Young L and Lee AV. Intrinsic subtype switching and acquired ERBB2/HER2 amplifications and mutations in breast cancer brain metastases. JAMA Oncol 3:666-671, 2017.
 
Bahreini A, Levine K, Santana-Santos L, Benos P, Wang P, Andersen C, Oesterreich S and Lee AV. Non-coding single nucleotide variants affecting estrogen receptor binding and activity. Genome Med 8:128, 2016.
Gyanchandani R, Lin Y, Lin HM, Cooper KL, Normolle DP, Brufsky AM, Fastuca M, Crosson W, Oesterreich S, Davidson NE, Bhargava R, Dabbs DJ and Lee AV. Intra-tumor heterogeneity affects gene expression profile test prognostic risk stratification in early breast cancer. Clin Cancer Res 22:5362-5369, 2016. 
Farabaugh SM, Chan BT, Cui X, Dearth RK and Lee AV. Lack of interaction between ErbB2 and insulin receptor substrate signaling in breast cancer. Cell Commun Signal 14:25, 2016. 
Katz TA, Liao S, V Palmieri,, Dearth RK, Pathiraja TN, Huo Z, Shaw P, Small S, Davidson NE, Peters DG, Tseng G,  Oesterreich S and Lee AV. Targeted DNA methylation screen in the mouse mammary genome reveals a parity-induced hypermethylation of IGF1R which persists long after parturition.  Cancer Prev Res 8:1000-1009, 2015.
 
 
Casa AJ, Hochbaum D, Sreekumar S, Oesterreich S and Lee AV. The estrogen receptor alpha nuclear localization sequence is critical for fulvestrant-induced degradation of the receptor. Mol Cell Endocrinol 415:76-86, 2015.