Abstract 3333: In vitro-based biochemical studies of erbb2 gene variation to address racial disparities in breast cancer mortality
Authors: He Wei , Saldana Matthew , Scharadin Tiffany , Hoang-Phou Steven , Trans Denise , Chang Dennis , Carraway Kermit , Henderson Paul , Coleman Matthew A. 
Published: May 2015

According to a 2012 study by the U.S. Center for Disease Control and Prevention (CDC), African-American women had a 41% higher rate of breast cancer mortality during 2005-2009 than did Caucasian women. Although overall cancer mortality rates have declined significantly in the U.S. since the early 1990s, the black-white mortality gap has been steadily growing. The underlying causes of this racial disparity are likely diverse, and include factors such as lower quality of care and reduced access to mammographic screening. However, more aggressive tumor biology may also contribute significantly to racial disparity in breast cancer outcomes.

Recently, a low frequency single nucleotide polymorphism (SNP) of the HER2 receptor tyrosine kinase, W452C, which occurs predominantly in African-American women (about 10% frequency), was significantly correlated with breast cancer. This study reported that tumors from patients harboring W452C do not amplify the erbB2 (HER2) gene or overexpress the protein, suggesting that this variant may contribute to breast cancer development through a mechanism distinct from the amplification common to HER2-positive breast cancer patients. Understanding the structural and functional differences associated with W452C will allow us to identify new strategies for customized breast cancer treatments for African American women.

To address the role of the W452C SNP in breast cancer we applied a cell-free in vitro reconstitution system that uses nanolipoprotein particles (NLPs) to solubilize and support functional membrane proteins. Cell-free produced wild type HER2 and W452C were tested for tyrosine phosphorylation as well as specific binding to therapeutic anti-HER2 monoclonal antibodies trastuzumab and pertuzumab. Our results showed comparable tyrosine phosphorylation levels for both wild type and W452C HER2, suggesting that the variant itself might not alone be a driver of cancer. We observed a decreased binding affinity of trastuzumab for W452C compared to wild type HER2, suggesting that W452-positive patients might not respond to trastuzumab treatment. On the other hand, we found that W452C has a higher affinity for pertuzumab. Overall, our studies suggest that the W452C variant may be differentially sensitive to clinically pertinent therapeutic agents. Further characterization of this variant will be important for the development of more effective and precise therapeutic interventions. This in turn could lead to targeted measures that help address racial disparity problems in breast cancer mortality.

Citation Format: Wei He, Matthew Saldana, Tiffany Scharadin, Steven Hoang-Phou, Denise Trans, Dennis Chang, Kermit Carraway, Paul Henderson, Matthew A. Coleman. In vitro-based biochemical studies of erbb2 gene variation to address racial disparities in breast cancer mortality. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3333. doi:10.1158/1538-7445.AM2014-3333