Focal amplifications involving chromosome 8p11-p12 occur in approximately 15% of human breast cancers. The fibroblast growth factor receptor 1 (FBFR1) gene has long been considered to be the best candidate oncogene at that locus. Three breast cancer cell lines developed in our lab; SUM-44, SUM-52 and SUM- 225, have overlapping amplicons centered around chromosome 8p11.2. FGFR1 is amplified in two of these cell lines, but is over expressed in only one of them. A second gene that maps to this region, transformation associated coiled-coiled protein 1 (TACC1), has recently been shown to be over expressed in some breast cancer cells and to have transforming activity in NIH3T3 cells. TACC1 is amplified and over expressed in all three of our cell lines. In addition to the FGFR1/TACC1 locus, SUM-52 and SUM-225 cells may each have distinct amplicons that center around 8p12 and 8q11.1 respectively. These regions contain several genes that are highly over expressed. Therefore, the broad aim of this proposal is to examine the prognostic and predictive significance of the 8p11-p12 amplicon in human breast cancer, and to identify genes therein that may be good targets for the development of novel therapeutics.
The specific aims of this project are: 1) To complete the fine mapping of the 8p11-p12 amplicon in the SUM-44, SUM-52, and SUM-225 cell lines by Southern blotting using probes for genes known to map to the region of gene amplification in each line, 2) To examine the expression levels of the amplified genes in each cell line by northern blot and RT-PCR, 3) To determine the predictive and/or prognostic significance of amplification of distinct regions of the 8p12-8q11 amplicon, and of specific candidate breast cancer genes, in breast cancer specimens using tissue micro arrays, 4) To test the mechanistic significance of genes found to be amplified and over expressed in the three breast cancer cell lines by transduction of candidate genes into immortalized human mammary epithelial cells, and by antisense techniques to down-regulate over expressed genes in breast cancer cells. Thus, these studies are aimed at defining new and better prognostic and predictive markers for an important subset of breast cancer, and at identifying causally relevant genes the products of which could be good targets for novel therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA100724-04
Application #
6897309
Study Section
Pathology B Study Section (PTHB)
Program Officer
Okano, Paul
Project Start
2003-06-01
Project End
2008-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
4
Fiscal Year
2005
Total Cost
$432,661
Indirect Cost
Name
Wayne State University
Department
Pathology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Turner-Ivey, Brittany; Smith, Ericka L; Rutkovsky, Alex C et al. (2017) Development of mammary hyperplasia, dysplasia, and invasive ductal carcinoma in transgenic mice expressing the 8p11 amplicon oncogene NSD3. Breast Cancer Res Treat 164:349-358
Irish, Jonathan C; Mills, Jamie N; Turner-Ivey, Brittany et al. (2016) Amplification of WHSC1L1 regulates expression and estrogen-independent activation of ER? in SUM-44 breast cancer cells and is associated with ER? over-expression in breast cancer. Mol Oncol 10:850-65
Wang, Guohui; Liu, Gang; Wang, Xiaogang et al. (2012) ERLIN2 promotes breast cancer cell survival by modulating endoplasmic reticulum stress pathways. BMC Cancer 12:225
Wu, J; Liu, S; Liu, G et al. (2012) Identification and functional analysis of 9p24 amplified genes in human breast cancer. Oncogene 31:333-41
Yang, Zeng-Quan; Liu, Gang; Bollig-Fischer, Aliccia et al. (2010) Transforming properties of 8p11-12 amplified genes in human breast cancer. Cancer Res 70:8487-97
Liu, G; Bollig-Fischer, A; Kreike, B et al. (2009) Genomic amplification and oncogenic properties of the GASC1 histone demethylase gene in breast cancer. Oncogene 28:4491-500
Yang, Zeng-Quan; Liu, Gang; Bollig-Fischer, Aliccia et al. (2009) Methylation-associated silencing of SFRP1 with an 8p11-12 amplification inhibits canonical and non-canonical WNT pathways in breast cancers. Int J Cancer 125:1613-21
Arias-Romero, Luis E; Saha, Sayanti; Villamar-Cruz, Olga et al. (2009) Activation of Src by protein tyrosine phosphatase 1B Is required for ErbB2 transformation of human breast epithelial cells. Cancer Res 69:4582-8
Willmarth, Nicole E; Baillo, Andrea; Dziubinski, Michele L et al. (2009) Altered EGFR localization and degradation in human breast cancer cells with an amphiregulin/EGFR autocrine loop. Cell Signal 21:212-9
Streicher, K L; Yang, Z Q; Draghici, S et al. (2007) Transforming function of the LSM1 oncogene in human breast cancers with the 8p11-12 amplicon. Oncogene 26:2104-14

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