Preclinical study

Breast Cancer Research and Treatment

, Volume 129, Issue 3, pp 717-724

Increased SIAH expression predicts ductal carcinoma in situ (DCIS) progression to invasive carcinoma

  • Kathryn C. BehlingAffiliated withDepartment of Pathology, Thomas Jefferson University and Kimmel Cancer Center Email author 
  • , Amy TangAffiliated withDepartments of Surgery and Biochemistry and Molecular Biology, Mayo Clinic Cancer Center, Mayo Clinic College of Medicine
  • , Boris FreydinAffiliated withDepartment of Pharmacology and Experimental Therapeutics, Thomas Jefferson University and Kimmel Cancer Center
  • , Inna ChervonevaAffiliated withDepartment of Pharmacology and Experimental Therapeutics, Thomas Jefferson University and Kimmel Cancer Center
  • , Sameep KadakiaAffiliated withDepartment of Pathology, Thomas Jefferson University and Kimmel Cancer Center
  • , Gordon F. SchwartzAffiliated withDepartment of Surgery, Thomas Jefferson University and Kimmel Cancer Center
  • , Hallgeir RuiAffiliated withDepartment of Cancer Biology, Thomas Jefferson University and Kimmel Cancer Center
  • , Agnieszka K. WitkiewiczAffiliated withDepartment of Pathology, Thomas Jefferson University and Kimmel Cancer Center

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Abstract

Hyperactivated HER2/Neu/EGFR/RAS signaling is a major growth-promoting pathway known to drive cellular transformation and oncogenesis in breast cancers. HER2 amplification is detected in ~20% of all human breast cancer and is quite prevalent (up to 49%) in ductal carcinoma in situ (DCIS). The E3 ubiquitin ligase SIAH is considered a key downstream “gatekeeper” required for proper HER2/EGFR/RAS signal transduction. Formalin-fixed, paraffin-embedded resection specimens from 65 patients with DCIS treated with wide excision only were stained with an anti-SIAH antibody, and the percentage of tumor and normal adjacent tissue cells positive for SIAH nuclear staining were recorded. Statistical analysis was performed comparing SIAH staining in tumor cells to disease recurrence, histologic type, necrosis, hormone receptor status, and Her2/neu status, as well as nuclear grade. Correlation of SIAH expression in tumor cells with SIAH expression in normal adjacent tissue and age was also examined. Expression levels of SIAH in tumor cells was significantly higher in specimens from patients with recurrence (median = 19%) as compared to patients without recurrence (7%) (P < 0.001). There was also significantly increased SIAH expression in tumors with more aggressive features including comedo morphology (13.5% in comedo vs. 7% in other histologic types, P = 0.014). No significant association was observed between SIAH expression and estrogen receptor, progesterone receptor, and Her2/neu status. There was a significant correlation between SIAH expression in tumors and normal adjacent tissue (Spearman correlation = 0.58, P < 0.001) as well as between SIAH expression in normal adjacent tissue and patient age (Spearman correlation = −0.59, P < 0.001). No significant correlation was identified between patient age and SIAH expression in tumors (Spearman correlation = −0.23, P = 0.067). In conclusion, SIAH may represent a useful prognostic biomarker that predicts DCIS progression to invasive breast cancer.

Keywords

SIAH Ductal carcinoma in situ DCIS