Transgenic mice with mammary gland targeted expression of human cortactin do not develop (pre-malignant) breast tumors: studies in MMTV-cortactin and MMTV-cortactin/-cyclin D1 bitransgenic mice.
BACKGROUND
In 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.


METHODS
MMTV-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.


RESULTS
Mammary 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.


CONCLUSIONS
From 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.
Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands. a.van.rossum@nin.knaw.nl
Agnes G S H
AG
van Rossum
Maaike P A
MP
van Bragt
Ellen
E
Schuuring-Scholtes
Jan C M
JC
van der Ploeg
Johan H J M
JH
van Krieken
Philip M
PM
Kluin
Ed
E
Schuuring
D000818:Animals; D051356:Cortactin / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D019938:Cyclin D1 / Q000235:genetics; D005260:Female; D015870:Gene Expression; D018390:Gene Targeting; D006801:Humans; D008321:Mammary Glands, Animal / Q000033:anatomy & histology / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology
C495868:CTTN protein, human; D051356:Cortactin; D019938:Cyclin D1