Significantly upregulated TACSTD2 and Cyclin D1 correlate with poor prognosis of invasive ductal breast cancer
Graphical abstract
Highlights
► The prognostic potential of TACSTD2 and Cyclin D1 was evaluated in IDC. ► High expression of TACSTD2 in IDC was related to Cyclin D1 status. ► TACSTD2, Cyclin D1 and lymph node metastasis were independent prognosis factors. ► TACSTD2 and Cyclin D1 correlate with lymph node metastasis and poor overall survival.
Introduction
Breast cancer is one of the most common neoplasms, accounting for approximately one quarter of all cancers in females (Coughlin and Ekwueme, 2009, Fattaneh et al., 2003). It is estimated that more than 1 million women are newly diagnosed every year, and more than 410,000 will die from this cancer worldwide (Coughlin and Ekwueme, 2009). China's urban cancer registries have documented that the incidence of breast cancer has increased 20% to 30% in the past decade (Porter, 2008). Early diagnosis and advances in therapy have begun to reduce mortality in several countries (Coughlin and Ekwueme, 2009, Fattaneh et al., 2003). Tumor markers could significantly alter the type of adjuvant treatment a patient receives and potentially impact the clinical outcome (Khoury et al., 2009). However, such information is not usually available and prognosis factors are needed to identify which patients might benefit from surgery, adjuvant systemic therapy, and/or other treatments (Baak et al., 2009). Since most of the currently available chemotherapeutic agents lack the ability to selectively target cancer cells, it is necessary to find more biological markers for predicting prognosis and molecular-targeted therapies in breast cancer (Fernández et al., 2010, Milacic and Dou, 2009, Schlotter et al., 2008).
Tumor-associated calcium signal transducer 2 (TACSTD2), also known as epithelial glycoprotein 1 (EGP1), as well as cell-surface glycoprotein Trop2 (Trop-2), membrane component chromosome 1 surface marker 1 (M1S1), and gastrointestinal tumor-associated antigen GA733-1 all belong to the tumor-associated calcium signal transducer (TACSTD) gene family (Basu et al., 1995, Calabrese et al., 2001, Fornaro et al., 1995, Linnenbach et al., 1989, Linnenbach et al., 1993, Ripani et al., 1998). TACSTD2 is identified as a single-copy gene in human cells, mapped to chromosome 1p32 by in situ hybridization (Calabrese et al., 2001, Linnenbach et al., 1989). It hybridizes to a single 1.8-kb mRNA from expressing sources and encodes a 35,709 Da type-1 transmembrane protein with a single transmembrane domain (Linnenbach et al., 1993). As a cell-surface glycoprotein first characterized on a human trophoblast cell, TACSTD2 may play a role in regulating the growth of carcinoma cells (Fornaro et al., 1995, Lipinski et al., 1981, Miotti et al., 1987). Nevertheless, its function has not yet been determined.
Recently, TACSTD2 has been reported to be highly expressed in various types of human carcinomas but rarely expressed in normal tissues, and also to be associated with tumor metastasis and poor prognosis of the patient (Bignotti et al., 2010, Cubas et al., 2009, Fang et al., 2009, Fong et al., 2008a, Fong et al., 2008b, Guerra et al., 2008, Mühlmann et al., 2009, Nakashima et al., 2004, Ohmachi et al., 2006). As no report had shown the correlation between the expression of TACSTD2 and prognosis in breast cancer, we examined the expression levels of TACSTD2 mRNA in a number of IDC tissues, using one-step quantitative real-time PCR.
Cyclin D1, an oncogene that has been linked to a less malignant phenotype, is highly expressed in many breast cancers (Lehn et al., 2010). P53, Ki-67, HER2, estrogen receptor (ER) and progesterone receptor (PR) have been traditionally recognized as poor prognostic factors and play significant roles in the management of patients for therapy (Taneja et al., 2010). We have characterized the expressions of TACSTD2 in IDC and adjacent non-malignant tissues. Furthermore, in this investigation we have elucidated the correlation of high TACSTD2 expression with clinicopathology and prognostic significance.
Section snippets
Tissue samples and patients
A panel of formalin-fixed, paraffin-embedded IDC tissues (n = 82) and tumor-adjacent non-malignant tissues (n = 70) were obtained from patients undergoing surgical therapy at the Affiliated Hospital of Nantong University between 2002 and 2007. Clinical data and relevant information were obtained from patient records. None of the patients had received neoadjuvant chemotherapy, radiation therapy, or immunotherapy before surgery. The tissue microarray (TMA) chips containing 152 cores of IDC and
Measurement of TACSTD2 mRNA and Cyclin D1 mRNA expression in breast tissues by One-step qPCR
Total RNA was extracted from the 15 IDC tissues and subjected to One-step qPCR to determine the expression of TACSTD2 mRNA and Cyclin D1 mRNA. To compare the expression of the mRNA with that of non-malignant tissue, we also investigated samples from the matched tumor adjacent tissues. When normalized to GAPDH, the means of TACSTD2 mRNA in breast cancer and corresponding non-cancerous tissue were 6.42 ± 5.697 and 2.34 ± 1.42 respectively (t = 4.5055, P < 0.001). The TACSTD2 expression averaged 2.74-fold
Discussion
TACSTD2 expression has been reported in various types of malignant neoplasms, including squamous cell carcinoma of the oral cavity (Fong et al., 2008a), esophageal carcinoma (Nakashima et al., 2004), gastric carcinoma (Mühlmann et al., 2009), colorectal cancer (Fang et al., 2009, Ohmachi et al., 2006), pancreatic cancer (Fong et al., 2008b), and ovarian carcinoma (Bignotti et al., 2010). These results indicated that a high expression of TACSTD2 showed prognostic value in those solid tumors.
Conflict of interest statement
The authors declare that there are no conflicts of interest.
Acknowledgments
This investigation was supported by grants from the National Natural Science Foundation of China (81101704), Jiangsu Natural Science Foundation, Nanjing, China (BK2008442), and Nanjing Medical Science and Technique Development Foundation, Nanjing, China (ZKX09015). We wish to thank the Affiliated Hospital of Nantong University for providing samples of patients.
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These authors contributed equally to this work.