Previous studies have shown that schizophrenics have decreased expression of α7-nicotinic acetylcholine (α7) receptors in the hippocampus and other brain regions, paranoid delusions, disorganized speech, deficits in auditory gating (i.e., inability to inhibit neuronal responses to repetitive auditory stimuli), and difficulties in odor discrimination and detection. Here we use mice with decreased α7 expression that also show a deficit in auditory gating to determine if these mice have similar deficits in olfaction.In the adult mouse olfactory bulb (OB), α7 expression localizes in the glomerular layer; however, the functional role of α7 is unknown. We show that inbred mouse strains (i.e., C3H and C57) with varying α7 expression (e.g., α7 wild-type [α7+/+], α7 heterozygous knock-out [α7+/−] and α7 homozygous knockout mice [α7−/−]) significantly differ in odor discrimination and detection of chemically related odorant pairs.Using [ 125 I] α-bungarotoxin (α-BGT) autoradiography, α7 expression was measured in the OB. As previously demonstrated, α-BGT binding was localized to the glomerular layer. Significantly more expression of α7 was observed in C57 α7+/+ mice compared to C3H α7+/+ mice. Furthermore, C57 α7+/+ mice were able to detect a significantly lower concentration of an odor in a mixture compared to C3H α7+/+ mice. Both C57 and C3H α7+/+ mice discriminated between chemically related odorants sooner than α7+/− or α7−/− mice. These data suggest that α7-nicotinic-receptors contribute strongly to olfactory discrimination and detection in mice and may be one of the mechanisms producing olfactory dysfunction in schizophrenics.

Down syndrome (DS) is the most common form of congenital intellectual disability. Although DS involves multiple disturbances in various tissues, there is little doubt that in terms of quality of life cognitive impairment is the most serious facet and there is no effective treatment for this aspect of the syndrome. The Ts65Dn mouse model of DS recapitulates multiple aspects of DS including cognitive impairment. Here the Ts65Dn mouse model of DS was evaluated in an associative learning paradigm based on olfactory cues. In contrast to disomic controls, trisomic mice exhibited significant deficits in olfactory learning. Treatment of trisomic mice with the acetylcholinesterase inhibitor galantamine resulted in a significant improvement in olfactory learning. Collectively, our study indicates that olfactory learning can be a sensitive tool for evaluating deficits in associative learning in mouse models of DS and that galantamine has therapeutic potential for improving cognitive abilities.

Introduction: Among the molecular subtypes of breast cancer are normal-like, luminal (A or B) estrogen receptor positive (ER+), HER2+, and triple negative (basal). In addition to the molecular subtypes, there are 18 histologic breast cancer subtypes that are classified on appearance, including mucinous breast cancers (MBC), which are ER+ tumors. MBC can be classified according to their mucin composition as pure mucinous (> 90% mucin) or mixed mucinous (50-90% mucin). We have established a new model of mucinous breast cancer using breast cancer cells derived from a pleural effusion of a patient that were xenografted into an immunocompromised mouse. The resulting cell line, BCK4, was subsequently implanted into mice supplemented with either cellulose or estrogen. Pure mucinous tumors (MUCp) formed in the presence of cellulose, however, estrogen induced a histologic switch to invasive lobular carcinoma (ILC) with mucinous features (mixed mucinous). These mixed mucinous tumors contained both high mucin (MUCm) and low mucin tumor regions (ILC). The purpose of this study was to determine the molecular underpinnings of this histologic switch in BCK4 tumors. Experimental procedures: We isolated an equal number of tumor cells from pure mucinous and both the MUCm and ILC regions of the mixed mucinous BCK4 tumors using LASER capture microdissection; samples were analyzed on Affymetrix arrays to examine differential gene regulation among the tumor regions. Summary: Approximately 3000 genes were differentially regulated between the mixed and pure mucinous tumors. PAM50 subtype calls for the different tumor regions were as follows: MUCp tumors are the Normal-like subtype, MUCm tumor regions are Normal-like/Luminal A, while the ILC regions of the mixed mucinous tumors were Luminal B/Basal. Cluster analysis of the BCK4 derived tumors compared with ER+ and ER- breast cancer cell lines shows the mixed mucinous BCK4 tumors (both MUCm and ILC regions) group with ER- breast cancers, while the pure mucinous tumors were more related to ER+ breast tumor cells. To elucidate early genes regulated by estrogen in BCK4 cells, we performed expression profiling using Illumina arrays of the BCK4 cell line, treated with or without estrogen in vitro for 24 hours. A set of ~200 genes were significantly regulated by estrogen in the BCK4 cell line and the BCK4 derived tumors. Metacore Pathway Analysis suggested the c-kit pathway might be a target to reduce estrogen-induced proliferation. Subsequent studies found that inhibition of c-kit activity using Imatinib Mesylate (Gleevec®) blocked estrogen mediated stimulation of BCK4 cells as effectively as the anti-estrogen Fulvestrant. Conclusions: Targeting c-kit may represent a new type of therapy for some mucinous breast cancers. This is the first study to examine estrogen regulated genes in a model of mucinous breast cancer, allowing identification of genetic pathways that cause more indolent pure mucinous tumors to switch to aggressive mixed mucinous tumors. Citation Format: J. Chuck Harrell, Megan J. Blatner, Britta M. Jacobsen. Inhibition of the invasive component of mucinous breast cancers by targeting c-kit. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A42.