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SCIENTIFIC REPORT 2010
MOLECULAR TARGETING
HEAD Elda Tagliabue, Biol Sci D STAFF MEMBERS
Manuela Campiglio, Biol Sci D Rosaria Orlandi, Biol Sci D Serenella M. Pupa, Biol Sci D TECHNICIANS
Pierangela Aiello, Patrizia Casalini (Responsible for DOSMM imaging facility), Cristina A. Ghirelli RESEARCH FELLOWS
Valentina Ciravolo, Biotech Sci D Gaia C. Ghedini, Biotech Sci Alessandra Meini, Biol Sci D Ilaria Plantamura, Biol Sci D Manuela Ratti, Biol Sci D Francesca Ripamonti, Biotech Sci D Tiziana Triulzi, Biotech Sci D (AIRC) PHD STUDENTS
Francesca Bianchi, Biotech Sci D (AIRC) Marilena V. Iorio, Biotech Sci D Marianna Sasso, Biol Sci D CONSULTANTS
Sylvie MĂŠnard, Biol Sci D Marco Sandri, Stat Sci D
During 2010, we focused on identification of new cancer-related antigens and investigated pathways driving development and progression of breast carcinoma. Concentrating our efforts on triple negative breast cancer (TNBC), we observed that these undifferentiated tumors present an endothelial-like phenotype. This property appears to be related to FGFR2, PDGFR- , and c-Kit. Inhibition of these receptors abrogated the in vivo growth of TNBC cell lines, indicating that these pathways might represent a specific therapeutic target. Investigating the role of microRNA in a model of TNBC, our results indicate that miR-205 has a strong suppressive function, inhibiting migration, cell proliferation, colony forming ability, and in vivo growth. In HER2+ breast carcinomas, we found that a HER2 splice variant lacking exon 16 (delta16HER2), which forms covalent cysteine bonds generating constitutively active homodimers on cell membrane, is constitutively expressed in human breast carcinomas in a proportion (about 9%) of WT HER2. Additionally, delta16HER2-expressing transfectants have increased transforming potency compared to WT HER2-expressing transfectants, and it was also found that only mice transgenic for the delta16HER2 isoform develop multiple spontaneous mammary carcinomas, demonstrating that delta16HER2 is a candidate for the transforming form of the HER2 oncoprotein. With the aim to identify HER2+ patients likely to benefit from trastuzumab therapy, we critically reassessed emerging data from clinical studies. The MAb appeared to act through multiple mechanisms, according to stage of the disease and treatment protocol. ADCC appears to be predominant when trastuzumab is used as monotherapy in neoadjuvant and metastatic settings; inhibition of DNA repair predominates in neoadjuvant and adjuvant settings involving concomitant trastuzumab and chemotherapy; whereas in sequential protocols, the monoclonal antibody appears to act primarily through cytostatic activity. Keywords: breast carcinoma, targeted therapy, HER2
2010 RELEVANT NOTES Collaborations Augusto Amici, Department of Molecular, Cellular and Animal Biology, University of Camerino (generation of delta16HER2 transgenic mice) Carlo M. Croce, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus OH (analysis of microRNA involved in the progression of triple negative breast carcinoma)
Publications Triple-negative breast cancer: Present challenges and new perspectives. Mol Oncol. 2010;4:209-29.