Functional redundancy between Apc and Apc2 regulates tissue homeostasis and prevents tumorigenesis in murine mammary epithelium.

Aberrant Wnt signaling within breast cancer is associated with poor prognosis, but regulation of this pathway in breast tissue remains poorly understood and the consequences of immediate or long-term dysregulation remain elusive. The exact contribution of the Wnt-regulating proteins adenomatous polyposis coli (APC) and APC2 in the pathogenesis of human breast cancer are ill-defined, but our analysis of publically available array data sets indicates that tumors with concomitant low expression of both proteins occurs more frequently in the 'triple negative' phenotype, which is a subtype of breast cancer with particularly poor prognosis. We have used mouse transgenics to delete Apc and/or Apc2 from mouse mammary epithelium to elucidate the significance of these proteins in mammary homeostasis and delineate their influences on Wnt signaling and tumorigenesis. Loss of either protein alone failed to affect Wnt signaling levels or tissue homeostasis. Strikingly, concomitant loss led to local disruption of ß-catenin status, disruption in epithelial integrity, cohesion and polarity, increased cell division and a distinctive form of ductal hyperplasia with 'squamoid' ghost cell nodules in young animals. Upon aging, the development of Wnt activated mammary carcinomas with squamous differentiation was accompanied by a significantly reduced survival. This novel Wnt-driven mammary tumor model highlights the importance of functional redundancies existing between the Apc proteins both in normal homeostasis and in tumorigenesis.

Context-driven changes in L-DOPA-induced behaviours in the 6-OHDA lesioned rat.

Both contralateral rotational behaviour and dyskinetic abnormal involuntary movements (AIMs) are induced by the administration of l-DOPA in the unilateral 6-OHDA lesioned rat model of Parkinson's disease. Since rotational responses can be conditioned to environmental cues we have investigated the extent to which drug-induced AIMS may also be conditioned by exteroceptive cues and experience. In Experiment I, 6-OHDA lesioned rats received repeated daily injections of l-DOPA either in their home cage (control) or in association with a brief (20 mins) exposure to the rotometers (paired). To assess conditioning, all animals then received two tests in the rotometer bowls. Following injection of saline the paired group both rotated more contralaterally and displayed manifest AIMs, neither of which were exhibited by the control rats. Moreover, following injection of l-DOPA, the paired group showed a trend for increased AIMs compared to controls. Two further studies provided longer exposure to the conditioning environments in counterbalanced designs. Although, using these parameters, re-exposure in the presence of saline did not induce context-dependent AIMs, a strong context-specific component of the sensitised response to l-DOPA was seen; chronic administration of drug produced a significantly stronger behavioural response in animals paired with a particular environment for drug administration than controls. This data suggests that part of the sensitisation of behavioural responding to l-DOPA administration is not solely a pharmacological phenomenon, but is also conditioned to the environmental context in which the drug is administered. This has clear implications for the clinical observation and experimental measurement of drug-induced dyskinesia in Parkinson's disease patients and animal models.