The study by CEINGE-Advanced Biotechnology researchers opens the way to early diagnosis and new possible therapies aimed at reducing the metastatic process of the most aggressive breast cancer
Triple negative breast cancer (TNBC) accounts for 20% of breast cancers and is also the most aggressive subtype, due to its clinical-pathological characteristics, including the young age of onset and the greater propensity to develop metastases. Patients with metastatic triple negative have a worse prognosis than those diagnosed with other subtypes of metastatic breast cancer: today there are no recognized molecular targets for therapy.
The study developed in the laboratories of the CEINGE-Advanced Biotechnology research center in Naples in collaboration with the Department of Molecular Medicine and Medical Biotechnology (University of Naples Federico II) and the Pathology Unit of the National Cancer Institute IRCS Fondazione Pascale demonstrated that the Prune-1 protein is over-expressed in about 50% of patients with triple negative breast cancer and is related to tumor progression, distant (lung) metastases and also to the presence of M2 macrophages (present in the tumor microenvironment of the TNBC and related to a higher risk of developing metastases).
The researchers also identified a small non-toxic molecule in the mouse model, which is able to inhibit the conversion of macrophages to the M2 phenotype and reduce the metastatic process in the lung.
An important milestone, reached by a team led by Massimo Zollo, geneticist, professor at the University of Naples Federico II and Principal Investigator of CEINGE, which includes, among others, two young researchers from Federico II and CEINGE Veronica Ferrucci and Fatemeh Asadzadeh (SEMM PhD student).
The first phase of the research involved the study of a genetically modified mouse model of metastatic TNBC, characterized by the over-expression of the PRUNE1 and WNT1 genes in the mammary gland. «The mouse model studied by us - explains Veronica Ferrucci - generates not only primary triple negative tumor, but also lung metastases. The mouse model allowed us to identify the presence of M2 type macrophages both in the primary tumor microenvironment and in the metastatic lung microenvironment ».
"Through the use of invasive breast cancer databases - adds Fatemeh Asadzadeh -., We have had confirmation that when these genes are over-expressed, worse prognoses occur. The process discovered in the mouse model may also be the same in the woman ».
"For us, a further" proof "was the presence of some genetic variants identified in the mouse model in human TNBC breast cancer samples present in databases but of unknown function now made known thanks to the studies obtained in the mouse model »Explains Massimo Zollo.
The molecule and the kit for early diagnosis
CEINGE researchers evaluated the efficacy against the progression of triple negative breast cancer of a small molecule, which has the ability to block the metastatic process in vivo. For this molecule, toxicity tests have already been performed in the mouse model. «This molecule is able to inhibit the conversion of macrophages towards the M2 phenotype and to reduce the metastatic process in the lung - explains Zollo -. Now the development of a second more sensitive molecule is being studied, which will have to be followed by experimentation in mice and then on humans. A kit has also been developed that is able to identify at the onset which TNBCs are most likely to develop lung-based and / or distant site metastases. This kit uses the genomic studies presented here and can help the oncologist determine a possibly more aggressive therapy from onset. It will take about 1-2 years of validation, so that it will be possible to demonstrate its effectiveness in clinical diagnosis.
The iSCIENCE study (CELL PRESS group) *
The research was published in the international scientific journal iSCIENCE (CELL PRESS group) and was funded by the European Union Project “PRIME-XS” and Tumic FP7, by the AIRC Association for Cancer Research, PON SATIN and by the Celeghin Foundation.
Among the institutions involved (in addition to CEINGE) the Department of Molecular Medicine and Medical Biotechnology DMMBM of the "Federico II", the Pathology Unit of the National Cancer Institute IRCS Pascale Foundation, the VIB-UGent medical biotechnology center (Belgium) , the Department of Public Health and the DAI Laboratory and Transfusion Medicine AOU Federico II and the European School of Molecular Medicine (SEMM).
The study was coordinated by prof. Massimo Zollo (University of Naples Federico II and CEINGE) in collaboration with prof. Kris Gevaert (Head of the Proteomics Center for Medical Biotechnologies VIB-UGent, Belgium), prof. Natascia Marino (Associate Professor, Indiana University, Indianapolis, USA) prof. Maurizio Di Bonito (Pathology Unit of the National Cancer Institute IRCS Pascale Foundation), prof. Giovanni Paolella (University of Naples Federico II and CEINGE) and prof. Francesco D'Andrea (Department of Public Health AOU Federico II).
* Prune-1 drives polarization of tumor-associated macrophages (TAMs) within the lungmetastatic niche in triple-negative breast cancer
Veronica Ferrucci, Fatemeh Asadzadeh, Francesca Collina, Roberto Siciliano, Angelo Boccia, Laura Marrone, Daniela Spano, Marianeve Carotenuto, Maria Cristina Chiarolla, Daniela De Martino, Gennaro De Vita, Alessandra Macrì, Luisa Dassi, Jonathan Vandenbussche, Natascia Marino, Monica Cantile , Giovanni Paolella, Francesco D'Andrea, Maurizio di Bonito, Kris Gevaert and Massimo Zollo