Abstract.The NBT-II rat carcinoma cell line exhibits two mutually exclusive responses to FGF-1 and EGF, entering mitosis at cell confluency while undergoing an epithelium-to-mesenchyme transition (EMT) when cultured at subconfluency. EMT is characterized by acquisition of cell motility, modifications of cell morphology, and cell dissociation correlating with the loss of desmosomes from cellular cortex. The pleiotropic effects of EGF and FGF-1 on NBT-II cells suggest that multiple signaling pathways may be activated. We demonstrate here that growth factor activation is linked to at least two intracellular signaling pathways. One pathway leading to EMT involves an early and sustained stimulation of pp60 ~src kinase activity, which is not observed during the growth factor-induced entry into the cell cycle. Overexpression of normal c-src causes a subpopulation of cells to undergo spontaneous EMT and sensitizes the rest of the population to the scattering activity of EGF and FGF-1 without affecting their mitogenic responsiveness. Addition of cholera toxin, a cAMP-elevating agent, severely perturbs growth factor induction of EMT without altering pp60 ..... activation, therefore demonstrating that cAMP blockade takes place downstream or independently of pp60Cs% On the other hand, overexpression of a mutated, constitutively activated form of pp60 csrc does not block cell dispersion while strongly inhibiting growth factor-induced entry into cell division. Moreover, stable transfection of a dominant negative mutant of c-src inhibits the scattering response without affecting mitogenesis induced by the growth factors. Altogether, these results suggest a role for pp60 csr~ in epithelial cell scattering and indicate that pp60 ¢src might contribute unequally to the two separate biological activities engendered by a single signal.CATTERING of epithelial cells has a central role in the control of embryogenesis, and in the process of carcinoma cell dispersion. The search for inducer molecules of epithelial cell scattering has led to the discovery of scatter factor (SF) that has been recognized to also behave as a mitogenic factor (54). Other proteins with scatter activity were first described as mitogens: for example, EGF, one of the first characterized growth factors is able to induce keratinocyte migration (2) and membrane ruffling of mammary carcinoma cells (4, 11). We previously demonstrated that several growth factors (FGF-I, EGF, TGF-a), all of which bind to tyrosine kinase receptors, are endowed with two distinct activities toward NBT-II cells. On subconfluent cultures, these growth factors generate a scattering response, characterized by several properties: cells loose their epithelial features, they become fibroblastic, and they dissociate and start moving individually (7,18,49). The entire spectrum of changes has been termed epi-
To investigate the expression and significance of proteasomes reactivator REG gamma (γ) in breast cancer. First, we showed the expression of REGγ in breast cancer, metastatic lymph nodes and normal breast tissues. Meanwhile, we also analyzed the relationship between REGγ and estrogen receptor (ER), CerBb-2, lymph nodes metastasis and clinical stage of breast cancer. REGγ expression was determined by immunohistochemical staining and western blot. Secondly, we detected the expression of REGγ and REGγ-mRNA in human breast cancer cell lines (MDA-MB-231, MCF-7) and human breast ductal epithelial cell line (HBL-100) by western blot and real-time PCR. Finally, in order to identify effect of REGγ on breast cancer cell cycle and proliferation, we constructed recombinant plasmid of PcDNA3.1-REGγ and designed siRNA for REGγ in vitro. Cell cycle was assayed by flow cytometer (FCM), proliferation was measured by methyl thiazolyl tetrazolium (MTT). The results demonstrated abnormal high expression of REGγ in breast cancer and its metastatic lymph nodes. REGγ expression was related to breast cancer and its status of ER, CerBb-2 and lymph nodes metastasis. REGγ is one of the potential markers in breast cancer. REGγ could facilitate the growth of breast cancer cells.
580 Background: BRCA1 being involved in DNA repair and apoptosis, its mutations may influence response to chemotherapy. In vitro studies demonstrated that loss of BRCA1 function increased sensitivity to platinum compounds and induced resistance to anthracyclines. BRCA1-related breast cancers tend to be ductal carcinomas with high tumor grade, absence of hormonal receptors and no HER2 overexpression, so called triple-negative. We retrospectively analyzed anthracycline-based neoadjuvant chemotherapy efficacy in triple- negative tumors according to BRCA1 status. Methods: 393 breast cancer pts were treated with FEC100 neoadjuvant chemotherapy (FU 500 mg/m2, epirubicine 100 mg/m2, cyclophosphamide 500 mg/m2) between 1/2000 and 12/2006. Out of them, 14% had a triple-negative phenotype (55 pts). Patients with young age at diagnosis or family history of breast cancer were offered genetic testing for BRCA1 and BRCA2 mutations. Twelve of these patients had a BRCA1 deleterious mutation with a triple-negative tumor. Characteristics of these 12 pts at diagnosis were: median age = 38, tumor stage = 7 T2N0, 2 T2N1, 2 T3N0, 1 T3N1. Results: Pathological complete response was defined as absence of invasive tumor in breast and axillary nodes. After 6 cycles of FEC100, 42% of patients with triple-negative tumors (23/55) had a pathological complete response, compared to 17% (2/12) with a BRCA1 mutation. Only one of the 12 BRCA1 patients had an axillary node involvement. Conclusions: In our series, BRCA1 deleterious mutations decreased anthracycline-based chemotherapy efficacy in triple- negative breast cancers. Platinum compounds should be evaluated in these BRCA1-related tumors. No significant financial relationships to disclose.
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