University of Kent, Canterbury, UK BSc 05/89 Biochemistry
ICRF, University of Surrey, Guildford, UK PhD 1993 Breast Biology
UT Health Science Center at San Antonio Postdoc 1997 Breast Cancer
I am an established investigator having published over 120 peer-reviewed manuscripts and a history of collaborative efforts (both wet and dry lab). The outstanding environment at the University of Pittsburgh will provide all the necessary facilities and resources needed to complete the research.
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.
1) Priedigkeit N, Watters RJ, Lucas PC, Basudan A, Bhargava R, Horne W, Kolls JK, Fang Z, Rosenzweig MQ, Brufsky AM, Weiss KR, Oesterreich S, Lee AV. Exome-capture RNA sequencing of decade-old breast cancers and matched decalcified bone metastases. JCI Insight. 2017 Sep 7;2(17). PMID: 28878133
2) Li Z, Levine KM, Bahreini A, Wang P, Chu D, Park BH, Oesterreich S, Lee AV. Upregulation of IRS1 enhances IGF1 response in Y537S and D538G ESR1 mutant breast cancer cells. Endocrinology. 2017 Sep 27. doi: 10.1210/en.2017-00693. [Epub ahead of print] PMID: 29029116
3) Bahreini A, Levine K, Santana-Santos L, Benos P, Wang P, Andersen C, Oesterreich S, Lee AV. Non-coding single nucleotide variants affecting estrogen receptor binding and activity. Genome Med. 2016 Dec 13;8(1):128.
4) 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, Lee AV. Breast cancer brain metastases show limited intrinsic subtype switching, yet exhibit acquired ERBB2 amplifications and activating mutations. JAMA Oncol. 2016 Dec 7. doi: 10.1001/jamaoncol.2016.5630
5) Farabaugh SM, Chan BT, Cui X, Dearth RK, Lee AV. Lack of interaction between ErbB2 and insulin receptor substrate signaling in breast cancer. Cell Commun Signal. 2016 Oct 21;14(1):25. PMID: 27765041 3.
6) Gyanchandani R, Lin Y, Lin HM, Cooper KL, Normolle DP, Brufsky AM, Fastuca M, Crosson W, Oesterreich S, Davidson NE, Bhargava R, Dabbs DJ, Lee AV. Intra-tumor heterogeneity affects gene expression profile test prognostic risk stratification in early breast cancer. Clin Cancer Res. 2016 Nov 1;22(21):5362-5369.PMID: 27185370
7) 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. 2015 Oct;8(10):1000-9 . Casa AJ, Hochbaum D, Sreekumar S, Oesterreich S, Lee AV. The estrogen receptor alpha nuclear localization sequence is critical for fulvestrant-induced degradation of the receptor. Mol Cell Endocrinol. 2015 Aug 10.