HER-2 gene products found in human breast cancer include the full-length p185 oncoprotein and various shorter isoforms that lack C-terminal, N-terminal or internal portions. Delta16 isoform lacks exon 16 and displays the properties of an activated oncogene. Transgenic mice expressing Delta16 in the mammary gland develop more mammary carcinomas, and at a younger age than mice transgenic for full-length HER-2. Human breast cancers, unlike transgenic mice, co-express Delta16 and full-length HER-2. To study mammary carcinogenesis in a mouse model that mimics the human situation, we obtained hybrid mice bearing heterozygous copies of both human transgenes (Delta16/HER-2 mice), and we compared them to parental mice (referred to as Delta16 and HER-2 transgenic mice, respectively). In Delta16/HER2 hybrid mice, mammary carcinogenesis was similar to that of Delta16 mice, with a median latency time of 17 weeks and a mean of 7 tumors per mouse, thus indicating a dominant expression of Delta16 over HER-2. However, after tumor onset, tumor growth rate and metastatic spread were similar in the three mouse lines, thus suggesting that Delta16 was mainly involved in neoplastic transformation and in the early phases of mammary carcinogenesis, rather than in advanced tumor progression. This could result from cancer cell intrinsic activity of the oncogene or from interactions with the microenvironment, in particular with vasculogenesis. Using isoform-specific PCR analysis we found that most tumors expressed only Delta16, some expressed both Delta16 and HER-2, and some expressed only HER-2. The level of Delta16 surface protein expression, as detected by FACS analysis with cross-reactive antibodies, was generally lower than that of HER-2. We established representative cell lines for in vitro studies. Exposure of these cells to trastuzumab, lapatinib, or their combination showed that Delta16 did not confer resistance to HER-2-targeted drugs in comparison to full-length HER-2. In conclusion, the study of Delta16/HER-2 double transgenic mice suggests that the activated isoform Delta16 plays a dominant role in the early phases of mammary carcinogenesis.
Coexpression of Delta16 isoform and full-length HER-2 in F1 hybrid transgenic mice: effects on tumor growth and malignancy
AMICI, Augusto;
2014-01-01
Abstract
HER-2 gene products found in human breast cancer include the full-length p185 oncoprotein and various shorter isoforms that lack C-terminal, N-terminal or internal portions. Delta16 isoform lacks exon 16 and displays the properties of an activated oncogene. Transgenic mice expressing Delta16 in the mammary gland develop more mammary carcinomas, and at a younger age than mice transgenic for full-length HER-2. Human breast cancers, unlike transgenic mice, co-express Delta16 and full-length HER-2. To study mammary carcinogenesis in a mouse model that mimics the human situation, we obtained hybrid mice bearing heterozygous copies of both human transgenes (Delta16/HER-2 mice), and we compared them to parental mice (referred to as Delta16 and HER-2 transgenic mice, respectively). In Delta16/HER2 hybrid mice, mammary carcinogenesis was similar to that of Delta16 mice, with a median latency time of 17 weeks and a mean of 7 tumors per mouse, thus indicating a dominant expression of Delta16 over HER-2. However, after tumor onset, tumor growth rate and metastatic spread were similar in the three mouse lines, thus suggesting that Delta16 was mainly involved in neoplastic transformation and in the early phases of mammary carcinogenesis, rather than in advanced tumor progression. This could result from cancer cell intrinsic activity of the oncogene or from interactions with the microenvironment, in particular with vasculogenesis. Using isoform-specific PCR analysis we found that most tumors expressed only Delta16, some expressed both Delta16 and HER-2, and some expressed only HER-2. The level of Delta16 surface protein expression, as detected by FACS analysis with cross-reactive antibodies, was generally lower than that of HER-2. We established representative cell lines for in vitro studies. Exposure of these cells to trastuzumab, lapatinib, or their combination showed that Delta16 did not confer resistance to HER-2-targeted drugs in comparison to full-length HER-2. In conclusion, the study of Delta16/HER-2 double transgenic mice suggests that the activated isoform Delta16 plays a dominant role in the early phases of mammary carcinogenesis.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
