Altered maternal profiles in corticotropin-releasing factor receptor 1 deficient mice

BACKGROUND: During lactation, the CNS is less responsive to the anxiogenic neuropeptide, corticotropin-releasing factor (CRF). Further, central injections of CRF inhibit maternal aggression and some maternal behaviors, suggesting decreased CRF neurotransmission during lactation supports maternal behaviors. In this study, we examined the maternal profile of mice missing the CRF receptor 1 (CRFR1). Offspring of knockout (CRFR1-/-) mice were heterozygote to offset possible deleterious effects of low maternal glucocorticoids on pup survival and all mice contained a mixed 50:50 inbred/outbred background to improve overall maternal profiles and fecundity. RESULTS: Relative to littermate wild-type (WT) controls, CRFR1-/- mice exhibited significant deficits in total time nursing, including high arched-back, on each test day. Consistent with decreased nursing, pups of CRFR1-deficient dams weighed significantly less than WT offspring. Licking and grooming of pups was significantly higher in WT mice on postpartum Day 2 and when both test days were averaged, but not on Day 3. Time off nest was higher for CRFR1-/- mice on Day 2, but not on Day 3 or when test days were averaged. Licking and grooming of pups did not differ on Day 2 when this measure was examined as a proportion of time on nest. CRFR1-/- mice showed significantly higher nest building on Day 3 and when tests were averaged. Mean pup number was almost identical between groups and no pup mortality occurred. Maternal aggression was consistently lower in CRFR1-/- mice and in some measures these differences approached, but did not reach significance. Because of high variance, general aggression results are viewed as preliminary. In terms of sites of attacks on intruders, CRFR1-/- mice exhibited significantly fewer attacks to the belly of the intruder on Day 5 and when tests were averaged. Performance on the elevated plus maze was similar between genotypes. Egr-1 expression differences in medial preoptic nucleus and c-Fos expression differences in bed nucleus of stria terminalis between genotype suggest possible sites where loss of gene alters behavioral output. CONCLUSION: Taken together, the results suggest that the presence of an intact CRFR1 receptor supports some aspects of nurturing behavior

Maternal Behavior is Impaired in Female Mice Lacking Type 3 Adenylyl Cyclase

Although chemosensory signals generated by mouse pups may trigger maternal behavior of females, the mechanism for detection of these signals has not been fully defined. As some odorant receptors are coupled to the type 3 adenylyl cyclase (AC3), we evaluated the role of AC3 for maternal behavior using AC3−/− female mice. Here, we report that maternal behavior is impaired in virgin and postpartum AC3−/− mice. Female AC3−/− mice failed the pup retrieval assay, did not construct well-defined nests, and did not exhibit maternal aggression. Furthermore, AC3−/− females could not detect odorants or pup urine in the odorant habituation test and were unable to detect pups by chemoreception. In contrast to wild-type mice, AC activity in main olfactory epithelium (MOE) preparations from AC3−/− female mice was not stimulated by odorants or pheromones. Moreover, odorants and pheromones did not evoke electro-olfactogram (EOG) responses in the MOE of AC3−/− female mice. We hypothesize that the detection of chemical signals that trigger maternal behavior in female mice depends upon AC3 in the MOE

Prolactin-induced mouse mammary carcinomas model estrogen resistant luminal breast cancer.

INTRODUCTION: Tumors that express estrogen receptor alpha (ERα+) comprise 75% of breast cancers in women. While treatments directed against this receptor have successfully lowered mortality rates, many primary tumors initially or later exhibit resistance. The paucity of murine models of this luminal tumor subtype has hindered studies of factors that promote their pathogenesis and modulate responsiveness to estrogen-directed therapeutics. Since epidemiologic studies closely link prolactin and the development of ERα+ tumors in women, we examined characteristics of the aggressive ERα+ and ERα- carcinomas which develop in response to mammary prolactin in a murine transgenic model (neu-related lipocalin- prolactin (NRL-PRL)). To evaluate their relationship to clinical tumors, we determined phenotypic relationships among these carcinomas, other murine models of breast cancer, and features of luminal tumors in women. METHODS: We examined a panel of prolactin-induced tumors for characteristics relevant to clinical tumors: histotype, ERα/progesterone receptor (PR) expression and estrogen responsiveness, Activating Protein 1 (AP-1) components, and phosphorylation of signal transducer and activator of transcription 5 (Stat5), extracellular signal regulated kinase (ERK) 1/2 and AKT. We compared levels of transcripts in the ERα-associated luminal signature that defines this subtype of tumors in women and transcripts enriched in various mammary epithelial lineages to other well-studied genetically modified murine models of breast cancer. Finally, we used microarray analyses to compare prolactin-induced ERα+ and ERα- tumors, and examined responsiveness to estrogen and the anti-estrogen, Faslodex, in vivo. RESULTS: Prolactin-induced carcinomas were markedly diverse with respect to histotype, ERα/PR expression, and activated signaling cascades. They constituted a heterogeneous, but distinct group of murine mammary tumors, with molecular features of the luminal subtype of human breast cancer. In contrast to morphologically normal and hyperplastic structures in NRL-PRL females, carcinomas were insensitive to ERα-mediated signals. These tumors were distinct from mouse mammary tumor virus (MMTV)-neu tumors, and contained elevated transcripts for factors associated with luminal/alveolar expansion and differentiation, suggesting that they arose from physiologic targets of prolactin. These features were shared by ERα+ and ERα- tumors, suggesting a common origin, although the former exhibited transcript profiles reflecting greater differentiation. CONCLUSIONS: Our studies demonstrate that prolactin can promote diverse carcinomas in mice, many of which resemble luminal breast cancers, providing a novel experimental model to examine the pathogenesis, progression and treatment responsiveness of this tumor subtype

Stress and breast cancer: from epidemiology to molecular biology

Stress exposure has been proposed to contribute to the etiology of breast cancer. However, the validity of this assertion and the possible mechanisms involved are not well established. Epidemiologic studies differ in their assessment of the relative contribution of stress to breast cancer risk, while physiological studies propose a clear connection but lack the knowledge of intracellular pathways involved. The present review aims to consolidate the findings from different fields of research (including epidemiology, physiology, and molecular biology) in order to present a comprehensive picture of what we know to date about the role of stress in breast cancer development