Abstract
BackgroundIn human breast cancers, amplification of chromosome 11q13 correlates with lymph node metastasis and increased mortality. To date, two genes located within this amplicon, CCND1 and EMS1, were considered to act as oncogenes, because overexpression of both proteins, respectively cyclin D1 and cortactin, correlated well with 11q13 amplification. Cyclin D1 is involved in cell cycle regulation and the F-actin-binding protein cortactin in cytoskeletal dynamics and cell migration. To study the role of cortactin in mammary gland tumorigenesis, we examined mouse mammary tumor virus (MMTV)-cortactin transgenic mice and MMTV-cortactin/-MMTV-cyclin D1 bitransgenic mice.MethodsMMTV-cortactin transgenic mice were generated and intercrossed with previously described MMTV-cyclin D1 transgenic mice. Immunohistochemical, Northern and Western blot analyses were performed to study the expression of human transgene cortactin during mammary gland development and in mammary tumors. For tumor incidence studies, forced-bred, multiparous mice were used to enhance transgene expression in the mammary gland. Microscopical examination was performed using haematoxylin and eosin staining.ResultsMammary gland tumors arose stochastically (incidence 21%) with a mean age of onset at 100 weeks. This incidence, however, did not exceed that of aged-matched control FVB/N mice (38%), which unexpectedly, also developed spontaneous mammary gland tumors. We mimicked 11q13 amplification by generating MMTV-cortactin/-MMTV-cyclin D1 bitransgenic mice but did not observe any synergistic effect of cortactin on cyclin D1-induced mammary hyperplasias or carcinomas, nor development of distant metastasis.ConclusionFrom this study, we conclude that development of (pre-malignant) breast tumors in either wild type or MMTV-cyclin D1 mice was not augmented due to mammary gland targeted overexpression of human cortactin.
Highlights
In human breast cancers, amplification of chromosome 11q13 correlates with lymph node metastasis and increased mortality
Total mRNA and protein were isolated from the abdominal mammary gland (MG) after 10-days of lactation
In transgenic line T16, the human cortactin transgene was highly expressed at both mRNA (Fig. 1C)
Summary
Amplification of chromosome 11q13 correlates with lymph node metastasis and increased mortality. Two genes located within this amplicon, CCND1 and EMS1, were considered to act as oncogenes, because overexpression of both proteins, respectively cyclin D1 and cortactin, correlated well with 11q13 amplification. Two genes located within this amplicon, EMS1, encoding cortactin, and CCND1 encoding cyclin D1, were both considered to act as oncogenes in breast cancer, because increased expression of both cortactin and cyclin D1 correlated well with 11q13 amplification [5,6,7]. Overexpression of cyclin D1 seems to have a causative role in breast cancer formation, since mice containing a mammary-gland targeted MMTV-cyclin D1 transgene develop mammary tumors at higher incidence (5 out of 9 transgenic mice compared to none of 15 non-transgenic controls) [14]. Cyclin D1 appears to be critical in some pathways of mammary tumorigenesis, because cyclin D1-deficient mice are resistant to breast cancers induced by the c-neu and Ha-ras oncogene, but remain fully sensitive to breast cancers induced by c-myc and Wnt-1 [18]
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