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Address correspondence to Robert E. Brown, M.D., Division of Laboratory Medicine, Geisinger Medical Center, Danville, PA 19822-0131, USA; tel 570 271 6332; fax 570 271 6105; e-mail rebrown{at}geisinger.edu.
Objective: To identify molecular events that occur concomitantly in HER-2/neu protein-receptor-positive breast carcinoma and to identify pathogenetic and growth-modulating sequences around its tyrosine-kinase-mediated cell proliferation and tumorigenesis that may be amenable to therapeutic interventions. Methods: Slides containing sections of 3 pelleted human breast carcinoma cell lines (DAKO HercepTest) and expressing HER-2/neu protein-receptor scored at 3+ (SKBR-3), 1+ (MDA-175), and 0 (MDA-231), respectively, were reacted in immunohistochemical procedures for the detection of the following antigens: HER-2, estrogen receptor (ER), progesterone receptor (PR), Ki-67, cyclin D1, c-Jun, epidermal growth factor receptor (EGFR), transforming growth factor (TGF)–
, components of the JAK/STAT signal transduction pathway (gp130, interleukin [IL]–6, and IL-11), p21ras, farnesyl transferase (FT), and potential growth inhibitory/proapoptotic and antiapoptotic-related proteins (latency-associated peptide [LAP] of TGF-ß1, TGF-ß receptor [R] II, p53, and bcl-2 and cyclooxygenase [COX]-2). Immunoreactivities were graded using bright-field microscopy on a scale of 0 to 3+. Results: Commonalities noted among the 3 cell lines include absent (0) chromogenic signals for ER and PR, relatively high Ki-67 proliferation indices (54, 40, and 61%, respectively), and positive signals (1 to 3+) for IL-6, IL-11, TGF-, EGFR, TGF-ß1 (LAP), TGF-ßRII,FT, p21ras, and p53. Strong intranuclear immunopositivities for cyclin D1 and c-Jun antigens were evident in the MDA-231 cell line but absent or rare (0 to ±) in SKBR-3. Conversely, gp130 antigen was readily detected in the SKBR-3 cell line but only weakly expressed (±) in MDA-231, whereas bcl-2 and COX-2 were expressed in the latter and not in SKBR-3 cells. Conclusions: These data suggest that signal transduction through farnesylated p21ras is part of the pathogenesis of tyrosine-kinase-mediated proliferation in HER-2/neu protein-receptor-positive breast carcinoma. Collaborations with the EGFR and JAK/STAT systems in these molecular events are also likely. Potential therapeutic agents include downregulators of c-erb-B1 (EGFR) and -B2 (HER-2) receptor expressions, inhibitors of tyrosine kinase and farnesylation, and activators of growth inhibitory/proapoptotic pathways.
Keywords: HER-2/neu, breast carcinoma, carcinogenesis, molecular pathways
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