title: Tyrosine kinase discoidin domain receptors DDR1 and DDR2 are coordinately deregulated in triple-negative breast cancer.
abstract: Receptor kinases Discoidin Domain Receptors (DDRs) 1 and 2 are emerging as new therapeutic targets in breast cancer (BC). However, the expression of DDR proteins during BC progression and their association with BC subtypes remain poorly defined. Herein we report the first comprehensive immunohistochemical analyses of DDR protein expression in a wide range of breast tissues. DDR1 and DDR2 expression was investigated by immunohistochemistry in 218 samples of normal breast (n = 10), ductal carcinoma in situ (DCIS, n = 10), and invasive carcinomas (n = 198), arrayed in tissue microarrays with comprehensive clinical and follow-up information. Staining was evaluated for cell type, subcellular localization, percentage and intensity (scores 1-4), and association with disease subtype and outcome. In normal epithelium and DCIS, DDR1 was highly expressed, while DDR2 was negative in normal epithelium, and in DCIS it localized to cells at the epithelial-stromal interface. Of the 198 invasive carcinomas, DDR1 was high in 87 (44 %) and low in 103 (52 %), and DDR2 was high in 110 (56 %) and low in 87 (44 %). High DDR2 was associated with high tumor grade (P = 0.002), triple-negative subtype (TNBC) (P < 0.0001), and worse survival (P = 0.037). We discovered a novel concordant deregulation of DDR expression, with a DDR1(Low)/DDR2(High) profile significantly associated with TNBC, compared to luminal tumors (P = 0.012), and with worse overall survival. In conclusion, DDR2 upregulation occurs in DCIS, before stromal invasion, and may reflect epithelial-stromal cross-talk. A DDR1(Low)/DDR2(High) protein profile is associated with TNBC and may identify invasive carcinomas with worse prognosis.
authors: Department of Pathology and Comprehensive Cancer Center, University of Michigan, 4217 Comprehensive Cancer Center, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109, USA.
authors: Kathy A
authors: KA
authors: Toy
authors: Rajeshwari R
authors: RR
authors: Valiathan
authors: Fernando
authors: F
authors: Núñez
authors: Kelley M
authors: KM
authors: Kidwell
authors: Maria E
authors: ME
authors: Gonzalez
authors: Rafael
authors: R
authors: Fridman
authors: Celina G
authors: CG
authors: Kleer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003131:Combined Modality Therapy; D000070818:Discoidin Domain Receptors; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D011379:Prognosis; D011485:Protein Binding; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011975:Receptors, Mitogen / Q000235:genetics / Q000378:metabolism*; D012307:Risk Factors; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D047368:Tumor Burden
chemical_list: D011975:Receptors, Mitogen; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases