HER-2/neu-Positive breast carcinoma: molecular concomitants by proteomic analysis and their therapeutic implications.
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)-alpha, 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-beta1, TGF-beta 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-alpha, EGFR, TGF-beta1 (LAP), TGF-betaRII,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 p21 ras 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.
Brown
Robert E
RE
Division of Laboratory Medicine, Geisinger Medical Center, Danville, PA 19822-0131, USA. rebrown@geisinger.edu
D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020543:Proteome / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D020543:Proteome; D018719:Erb-b2 Receptor Tyrosine Kinases