Abstract
The 8p11-12 chromosome region is one of the regions most frequently amplified in breast carcinoma (10-15% of cases). Several genes within this region have been identified as candidate oncogenes, as they are both amplified and overexpressed. However, very few studies have explored the role of these genes in cell transformation, with the aim of identifying valuable therapeutic targets. An analysis of comparative genomic hybridization array and expression profiling data for a series of 152 ductal breast carcinomas and 21 cell lines identified five genes (LSM1, BAG4, DDHD2, PPAPDC1B, and WHSC1L1) within the amplified region as consistently overexpressed due to an increased gene copy number. The use of small interfering RNA to knock down the expression of each of these genes showed the major role played by two genes, PPAPDC1B and WHSC1L1, in regulating the survival and transformation of two different cell lines harboring the 8p amplicon. The role of these two genes in cell survival and cell transformation was also confirmed by long-term knockdown expression studies using short hairpin RNAs. The potential of PPAPDC1B, which encodes a transmembrane phosphatase, as a therapeutic target was further shown by the strong inhibition of growth of breast tumor xenografts displaying 8p11-12 amplification induced by the silencing of PPAPDC1B. The oncogenic properties of PPAPDC1B were further shown by its ability to transform NIH-3T3 fibroblasts, inducing their anchorage-independent growth. Finally, microarray experiments on PPAPDC1B knockdown indicated that this gene interfered with multiple cell signaling pathways, including the Janus-activated kinase-signal transducer and activator of transcription, mitogen-activated protein kinase, and protein kinase C pathways. PPAPDC1B may also potentiate the estrogen receptor pathway by down-regulating DUSP22.
Highlights
Recurrent chromosomal alterations are a hallmark of cancer cells and represent critical events in tumor development
We focused our study on the chromosome 8 amplicon and delineated a 3.2-Mb region of DNA amplification on chromosome 8p11-12 common to 11 of the 152 infiltrating ductal breast carcinomas (7.2%) and to 3 of the 21 breast cancer cell lines (14%) studied (Fig. 1A and B)
Affymetrix DNA microarrays were used to analyze RNA levels in 128 of the 152 breast carcinomas, in 18 of the 21 cell lines studied on comparative genomic hybridization (CGH) arrays, and in 11 normal breast samples
Summary
Recurrent chromosomal alterations are a hallmark of cancer cells and represent critical events in tumor development. Major recurrent amplicons include 17q12 (ERBB2/HER-2), 8q24 (MYC), 11q13 (CCND1), 20q13, and 8p11-12 [4]. The 17q12 amplicon, which has been extensively characterized, provides a clear illustration of the potential of tumor genomics for identifying drug targets. This amplification consistently leads to overexpression of the ERBB2 receptor, which can be efficiently targeted by specific inhibitors, such as Herceptin, used to treat ERBB2-positive breast carcinoma [5]. Major efforts are under way to characterize potential drug targets in other breast cancer amplicons [6,7,8]
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