Cells expressing HCCR-1 are tumorigenic in nude mice . The functional role of this oncogene in tumorigenesis is manifested as a negative regulator of the p53 tumor suppressor . In the previous study, we investigated HCCR-1 protein expression in breast cancer and the possibility of using HCCR-1 as a useful biomarker for human breast cancer . We also examined whether HCCR-1 protein expression in breast cancer is related to different biological characteristics including ER, PR, p53 genotype, and the HER2 status. Northern and Western blot analyses and immunohistochemical studies indicate that the HCCR-1 mRNA and protein are overexpressed in breast cancer tissues compared to the normal breast tissues [1, 2]. Serological studies revealed an 86.8% sensitivity for HCCR-1 in breast cancer, which was higher than 21.0% for CA15-3 [2, 3]. The HCCR-1 assay has an advantage over CA15-3 in diagnosing breast cancer. These results indicate that HCCR-1 is an oncoprotein that is related to breast cancer development [1, 2].
Overexpression of human epidermal growth factor receptor type 2 (HER2, also referred to as HER2/neu or ErbB-2), a 185-kD receptor first described more than two decades ago , occurs in 20 to 30% of invasive breast cancers. In general, patients with breast-cancer cells that overexpress this receptor or that have a high copy number of its gene have decreased overall survival and may have differential responses to a variety of chemotherapeutic and hormonal agents [5, 6]. Thus, strategies to target HER2 appear to be important in treating breast cancer . HER2 signaling promotes cell proliferation through the RAS-MAPK pathway and inhibits cell death through the phosphatidylinositol 3'-kinase-AKT-mammalian target of rapamycin (mTOR) pathway . Likewise, the HCCR-1 signaling is also known to be regulated by the phosphatidylinositol 3'-kinase-AKT pathway .
According to our previous study using a panel of breast cancer cell lines , HCCR-1 was highly expressed in breast cancer cell lines with high HER2 overexpression, with some exceptions, that have a mutated p53 and express ER/PR [10–13]. These data indicate that the HCCR-1 overexpression in breast cancer cell lines is well correlated with known breast cancer prognostic markers including high HER2 overexpression [10–13].
Because HER2 overexpression and amplification have important consequences on the prognosis and treatment of breast cancer, their presence must be accurately determined. Currently, two different methods are being used worldwide, immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). These two techniques identify different targets and both have advantages and disadvantages . Which method should be viewed as the gold standard for HER2 determination remains a debate. Recently, other methods have been described as options for HER2 testing. Real time polymerase chain reaction (RT-PCR)  and chromogen in situ hybridization (CISH)  have been proposed as cheaper and easier alternatives to FISH. Acceptable correlations between both methods and FISH have been reported . But the correlations among the various clinical methods of detecting HER2 are imperfect with regard to both prognostication and the prediction of a response to trastuzumab (Herceptin, Genentech).
Multiple studies have demonstrated marked improvement in disease-free and overall survival when trastuzumab is incorporated in therapeutic regimens for HER2 overexpressed tumors [17, 18]. Only patients whose tumors strongly overexpress HER2 by immunohistochemistry (IHC) and/or have amplification of the cerb2 gene by FISH, are likely to respond to Herceptin treatment .
Testing invasive breast carcinomas for HER2 overexpression/gene amplification has become a standard of practice . Much of the recent literature has focused on the best method for documenting HER2 overexpression (IHC vs. FISH), technical limitations of each method, and the need for consistency and QA in test performance [17, 21–23]. The National Comprehensive Cancer Network HER2 Testing in Breast Cancer Task Force concluded that where adequate quality control/quality assurance procedures are followed, either IHC or FISH are acceptable methods .
Whether a laboratory uses IHC with FISH for equivocal cases, or uses FISH as the initial HER2 screen, these tests are expensive to perform. Development of a rational approach to selecting cases for HER2 testing would promote cost effectiveness in the health care system .
The aim of this study is to analyze the level of HCCR-1 expression in breast cancer tissues in order to demonstrate its correlation to other biomarkers including ER, PR, p53, and HER2, and estimate the possibility of HCCR-1 as a new biomarker candidate for breast cancer.