Abstract
Breast cancer is a heterogeneous disease with distinct molecular subtypes characterized by differential response to targeted and chemotherapeutic agents. Enhanced understanding of the genetic alterations characteristic of different subtypes is needed to pave the way for more personalized administration of therapeutic agents. We have taken a functional genomics approach using a well-characterized panel of breast cancer cell lines to identify putative biomarkers of resistance to antimitotic agents such as paclitaxel and monomethyl-auristatin-E (MMAE). In vitro studies revealed a striking difference in sensitivity to these agents between cell lines from different subtypes, with basal-like cell lines being significantly more sensitive to both agents than luminal or HER2-amplified cell lines. Genome-wide association studies using copy number data from Affymetrix single nucleotide polymorphism arrays identified amplification of the chromosome 17q21 region as being highly associated with resistance to both paclitaxel and MMAE. An unbiased approach consisting of RNA interference and high content analysis was used to show that amplification and concomitant overexpression of the gene encoding the ABCC3 drug transporter is responsible for conferring in vitro resistance to paclitaxel and MMAE. We also show that amplification of ABCC3 is present in primary breast tumors and that it occurs predominantly in HER2-amplified and luminal tumors, and we report on development of a specific fluorescence in situ hybridization assay that may have utility as a predictive biomarker of taxane resistance in breast cancer.
Highlights
A key goal of modern molecular oncology is identifying the underlying genetic and genomic abnormalities that characterize a given tumor so that the patient can receive targeted and chemotherapeutic agents likely to provide the most benefit
Affymetrix gene expression profiling was performed on cDNA prepared from total mRNA and Affymetrix 100 K single nucleotide polymorphism (SNP) array profiling was done on DNA from 44 breast cancer cell lines
Our findings agree with previous reports [13] and suggest that this collection of breast cancer cell lines reflects to some degree the major transcriptional distinctions that define breast cancer subtypes and to some extent are representative as models of subtypes as luminal, basal-like, and HER2-amplified tumors
Summary
A key goal of modern molecular oncology is identifying the underlying genetic and genomic abnormalities that characterize a given tumor so that the patient can receive targeted and chemotherapeutic agents likely to provide the most benefit. Doi:10.1158/0008-5472.CAN-08-0234 therapies such as tamoxifen for estrogen receptor (ER)–positive cancer [2] and Herceptin for tumors harboring amplification of the HER2 oncogene [3] has had significant effect on patient survival; yet, various chemotherapy regimens still form an important component of breast cancer treatment [4]. Chemotherapy is a successful treatment regimen in many cases, an estimated 50% of patients fail to benefit due to intrinsic or acquired multidrug resistance Understanding the molecular alterations that contribute to MDR in breast cancer will be a crucial first step in enabling the development of diagnostic tests capable of predicting resistance to a given therapy and rationally selecting more efficacious therapeutic agents
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