Role of imatinib in hormone-dependent breast cancer angiogenesis

• Autor(es): Rocha, Ana Sofia Costa Gomes da
• Data: 2011
• Identificador Persistente: http://hdl.handle.net/10216/22101
• Origem: Repositório Aberto da Universidade do Porto
• Assunto(s): Medicina e Oncologia Molecular; Porto
• Tipo de Documento: Dissertação de mestrado
• Idioma: Português

Descrição

In previous studies, we found that progesterone was able to induce the expression of platelet-derived growth factor A (PDGF-A) in human breast cancer MCF7 cells. Knowing that PDGF plays a relevant role in angiogenesis, and that imatinib mesylate targets PDGF receptor tyrosine kinase activity, the aim of the present study was to examine the effects of imatinib on progesterone-treated MCF7 cells, Human Aortic Smooth Muscle Cells (HAoSMC) and Human Umbilical Vein Endothelial Cells (HUVEC). Expression of phosphorylated (activated) PDGFR- was detected in MCF7 cells and HAoSMC, but in a very low extent in HUVEC. The effects of imatinib on cell growth, apoptosis and migration were then analyzed. In MCF7 cells imatinib effectively inhibited anchorage-dependent colony formation, and cell viability as evaluated by MTT assay. Corroborating these findings, a significant increase in the percentage of apoptotic cells was observed when MCF7 cells were treated with imatinib. Surprisingly, these inhibitory effects were all enhanced by the presence of progesterone. Cell migration assays in MCF7 cells did also show a reduction in the migratory capacity after incubation with imatinib. In agreement with the lack of active PDGFR- , imatinib was unable to prevent HUVEC growth, survival or migration ability. In contrast, HAoSMC viability and proliferation were effectively inhibited by imatinib, as evaluated by MTT and BrdU assay, respectively. Supporting these findings, a significant increase in the percentage of apoptotic HAoSMC was also observed after treatment with imatinib. Cell migration assays did also show a reduction in the migratory ability after incubation with imatinib. Altogether, these facts reveal that imatinib is able to affect MCF7 and HAoSMC survival, growth and migration. Furthermore, incubation with progesterone seems to sustain PDGFR activity, prompting these cells to the inhibitory action of imatinib. Our findings indicate that imatinib might be a good therapeutic agent in progesterone-dependent breast cancer and, possibly, against other vascular-associated disorders, such as atherosclerosis, that carry in common smooth muscle cells abnormal growth.