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Di Bonito M.,INT Fondazione Pascale | Cantile M.,INT Fondazione Pascale | Collina F.,INT Fondazione Pascale | Scognamiglio G.,INT Fondazione Pascale | And 5 more authors.
Journal of Breast Cancer | Year: 2012

Purpose: Triple-negative breast cancer, has a significant clinical relevance being associated with a shorter median time to relapse and death and does not respond to endocrine therapy or other available targeted agents. For this reason, identifying the molecular pathways associated with increased aggressiveness, for example the presence of stem cell populations within the tumor and alteration of genes associated with cell cycle regulation represents an important objective in the clinical research into this neoplasm. Methods: To investigate the role of cell cycle progression inhibitor Geminin in triple-negative breast cancers and its potential correlation with stem-like phenotype of this neoplasm, we used tissue microarray technology to build a specific triplenegative breast cancer tissue micro-array. Geminin and cancer stem cell marker CD133 expression was further investigated at the mRNA level for selected breast tumor samples through realtime polymerase chain reaction quantification. Results: Our results showed that CD133 expression was significantly associated to high Geminin expression (p=0.017), a strong association between Ki-67 and tumor grade (p=0.020) and an inverse association between Geminin expression and lymphonode metastases (p= 0.058), and a trend of statistically significance between Geminin marker expression and survival of triple-negative breast cancer patients (p=0.076). Conclusion: The strong association between the expression of CD133 and Geminin could be useful in molecular stratification of breast tumors and in particular of triple-negative breast cancers. © 2012 Korean Breast Cancer Society. All rights reserved.


PubMed | INT Fondazione Pascale
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

3119 Background: Clinical studies of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) as monotherapy in breast cancer patients have shown some evidence of activity. Significant relief of bone pain in patients with bone metastases was observed in a clinical trial of the EGFR-TKI gefitinib (IRESSA) in patients with metastatic breast cancer.The expression and functional role of EGFR, as well as the effects of gefitinib (4 M) on the ability to produce osteoclastogenic factors, were investigated by reverse-transcriptase PCR, Real-Time PCR, Western blot analysis, immunoprecipitation, and/or ELISAs in 2 human bone marrow-derived continuous mesenchymal-stem-cell-like cell lines, HDS-1 and HDS-2.Immunohistochemical analysis of bone marrow biopsies showed that human primary bone marrow stromal cells (BMSC) express immunoreactive EGFR. Expression of EGFR mRNA and protein was also demonstrated in both HDS cell lines. The levels of activated EGFR were significantly increased in HDS cells following treatment with EGF; this activation was blocked by gefitinib. Gefitinib reduced basal levels of activated EGFR and Akt in HDS cells. Treatment of HDS cells with gefitinib significantly reduced levels of secreted macrophage colony-stimulating factor (p<0.001, Student t-test) and cell-associated receptor activator of NF-kB ligand (RANKL) [p<0.05, Student t-test]. In contrast, no significant effects of gefitinib on the secretion of osteoprotegerin, a RANKL decoy receptor that inhibits osteoclast differentiation, were observed in HDS cells. Finally, the ability of conditioned medium from gefitinib-treated HDS cells to sustain the differentiation of pre-osteoclasts was reduced by 45% compared with untreated HDS cells (p<0.001, Student t-test).These data demonstrate that EGFR regulates the ability of BMSC to induce osteoclast differentiation and strongly support clinical trials of gefitinib in patients with breast cancer and bone metastases. IRESSA is a trademark of the AstraZeneca group of companies [Table: see text].


PubMed | INT Fondazione Pascale
Type: Journal Article | Journal: Journal of breast cancer | Year: 2012

Triple-negative breast cancer, has a significant clinical relevance being associated with a shorter median time to relapse and death and does not respond to endocrine therapy or other available targeted agents. For this reason, identifying the molecular pathways associated with increased aggressiveness, for example the presence of stem cell populations within the tumor and alteration of genes associated with cell cycle regulation represents an important objective in the clinical research into this neoplasm.To investigate the role of cell cycle progression inhibitor Geminin in triple-negative breast cancers and its potential correlation with stem-like phenotype of this neoplasm, we used tissue microarray technology to build a specific triple-negative breast cancer tissue micro-array. Geminin and cancer stem cell marker CD133 expression was further investigated at the mRNA level for selected breast tumor samples through realtime polymerase chain reaction quantification.Our results showed that CD133 expression was significantly associated to high Geminin expression (p=0.017), a strong association between Ki-67 and tumor grade (p=0.020) and an inverse association between Geminin expression and lymphonode metastases (p=0.058), and a trend of statistically significance between Geminin marker expression and survival of triple-negative breast cancer patients (p=0.076).The strong association between the expression of CD133 and Geminin could be useful in molecular stratification of breast tumors and in particular of triple-negative breast cancers.

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