Abstract LB-18: Expression of discoidin domain receptor tyrosine kinases in breast cancer

Abstract

Abstract A key step in breast cancer progression is the transition from in situ to invasive carcinoma. This process is partly mediated by defective interactions between the epithelial cells and the extracellular matrix, leading to loss of cell-cell contacts and polarity, increased proliferation, and acquisition of invasive activity. Here we report that a unique set of receptor tyrosine kinases (RTKs) known as the discoidin domain receptors (DDRs) may play a key role during the transition of in situ to invasive breast carcinoma. DDRs are the only RTKs that recognize collagen as their ligands and thus mediate collagen-initiated signaling in both physiological and pathological conditions. The expression of DDRs at various stages of breast cancer progression is unknown. We used a high-density tissue microarray containing samples of normal breast, ductal carcinoma in situ (DCIS), and invasive carcinomas of different clinico-pathological characteristics to examine the expression of DDR1 by immunohistochemistry using an antibody to the C-terminus of DDR1. Expression of DDR1 was evaluated taking into consideration the percentage and intensity of staining, and categorized as low or high. DDR1 was highly expressed in the cytoplasm and membrane of normal epithelial cells in ducts and acini, and in DCIS. In contrast, 88 of 134 (66%) invasive carcinomas displayed low or absent DDR1 expression, while 44% exhibited high levels. DDR1 expression was not associated with histologic type, grade, hormonal receptor or HER2-neu status. Interestingly, 15 of 40 (37.5%) patients with high DDR1 expression developed tumor recurrence compared to 9 of 46 (19.6%) patients with low DDR1 (Kaplan Meier log-rank p=0.05). The expression of DDR1 was also evaluated in a mouse model of breast cancer progression using pre-neoplastic and malignant human MCF10A cell variants. DDR1 was highly expressed in the benign hyperplastic lesions generated by MCF10AT1 cells, and in the comedo DCIS tumors generated by MCF10DCIS.COM cells. In contrast, low or no DDR1 expression was observed in tumors generated by the highly malignant MCF10CA1 variant. Expression analyses of DDR1 isoforms in cultured cells by real-time PCR demonstrated that non-malignant MCF10A cells expressed higher levels of DDR1b mRNA while malignant MCF10CA1 cells showed higher levels of DDR1a suggesting that malignant progression is associated with a DDR1 isoform switch. At present the functional roles of the DDR1 isoforms in breast cancer progression remain unknown. Our analyses suggest that loss of or reduced DDR1 expression is associated with the transition from in situ to invasive carcinomas while patients with invasive carcinomas displaying high DDR1 expression have worse disease free survival. These novel studies highlight a complex role of DDR1 in breast cancer progression that deserves further exploration. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-18. doi:1538-7445.AM2012-LB-18