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Genomics, epigenomics, and transcriptomics in breast cancer

We produced the first base-pair level map of structural rearrangements in MCF-7 breast cancer cells (a). We have shown the importance of long insert mate-pair sequencing for resolving complex rearrangements in highly repetitive regions of the genome (b). We showed an interaction between the genome and epigenome (c), and that non-coding changes in the genome can affect estrogen receptor action (d). Following on from our work showing that pregnancy alters long-term GH/IGF action (e), we used whole genome bisulfite sequencing to show that the epigenome is altered following pregnancy in the mouse (f) and important in aromatase inhibitor resistance in breast cancer (g). We are currently using RNA exome sequencing (h) to identify changes in gene expression and RNA fusions in advanced breast cancer (i).

a.            Hampton OA, Den Hollander P, Miller CA, Delgado DA, Li J, Coarfa C, Harris RA, Richards S, Scherer SE, Muzny DM, Gibbs RA, Lee AV, Milosavljevic A. A sequence-level map of chromosomal breakpoints in the MCF-7 breast cancer cell line yields insights into the evolution of a cancer genome. Genome research. 2009 Feb;19(2):167-77. PMID: 19056696. PMCID: 2652200.

b.            Hampton OA, Koriabine M, Miller CA, Coarfa C, Li J, Den Hollander P, Schoenherr C, Carbone L, Nefedov M, Ten Hallers BF, Lee AV, De Jong PJ, Milosavljevic A. Long-range massively parallel mate pair sequencing detects distinct mutations and similar patterns of structural mutability in two breast cancer cell lines. Cancer genetics. 2011 Aug;204(8):447-57. PubMed PMID: 21962895. Pubmed Central PMCID: 3185296.

c.             Coarfa C, Pichot C, Jackson A, Tandon A, Amin V, Raghuraman S, Paithankar S, Lee AV, McGuire SE, Milosavljevic A. Analysis of interactions between the epigenome and structural mutability of the genome using Genboree Workbench tools. BMC bioinformatics. 2014;15 Suppl 7:S2. PubMed PMID: 25080362. Pubmed Central PMCID: 4110728.

d.            Bahreini A, Levine K, Santana-Santos L, Benos PV, Wang P, Andersen C, Oesterreich S, Lee AV. Non-coding single nucleotide variants affecting estrogen receptor binding and activity. Genome Med. 2016;8(1):128. PMID: 27964748

e.            Dearth RK, Delgado DA, Hiney JK, Pathiraja T, Oesterreich S, Medina D, Dees WL, Lee AV.  Parity-induced decrease in systemic growth hormone alters mammary gland signaling: a potential role in pregnancy protection from breast cancer. Cancer Prev Res (Phila). 2010 Mar;3(3):312-21. doi: 10.1158/1940-6207.CAPR-09-0074. PMID: 20145191

f.              Katz TA, Liao SG, Palmieri VJ, Dearth RK, Pathiraja TN, Huo Z, Shaw P, Small S, Davidson NE, Peters DG, Tseng GC, Oesterreich S, Lee AV. Targeted DNA Methylation Screen in the Mouse Mammary Genome Reveals a Parity-Induced Hypermethylation of Igf1r That Persists Long after Parturition. Cancer Prev Res. 2015 Oct;8(10):1000-9. PMID: 2629039

g.            Pathiraja TN, Nayak SR, Xi Y, Jiang S, Garee JP, Edwards DP, Lee AV, Chen J, Shea MJ, Santen RJ, Gannon F, Kangaspeska S, Jelinek J, Issa JP, Richer JK, Elias A, McIlroy M, Young LS, Davidson NE, Schiff R, Li W, Oesterreich S. Epigenetic reprogramming of HOXC10 in endocrine-resistant breast cancer. Sci Transl Med. 2014 Mar 26;6(229). PMID: 24670685

h.            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 Identifies Clinically Actionable Targets. JCI Insight. 2017 Sep 7;2(17). PMID: 28878133

i.              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. 2017;3(5):666-671.