Mice harboring three mouse mammary tumor virus (MMTV) variants develop pregnancy-dependent (PD)tumors that progress to pregnancy-independent (PI) behavior through successive passages. Herein, we identified 10 predominant insertions in PI transplants from 8 independent tumor lines. These mutations were also detected in small cell populations in the early PD passages. In addition, we identified a new viral insertion upstream of the gene Rspo3, which is overexpressed in three of the eight independent tumor lines and codes for a protein very similar to the recently described protein encoded by Int7. This study suggests that during progression towards hormone independence, clonal expansion of cells with specific mutations might be more relevant than the occurrence of new MMTV insertions.The mechanisms underlying breast cancer progression can be studied using mouse models susceptible to developing mammary tumors. With the BALB/c strain, three recently discovered mouse mammary tumor virus (MMTV) variants (BALB/2, BALB/14, and LA) induce pregnancy-dependent (PD) mammary tumors (4, 10), which eventually progress to a pregnancy-independent (PI) behavior. Infected pregnant females were examined in order to detect pregnancy-dependent primary tumors. Individual tumors (tumor area, ϳ50 mm 2 ) were minced in sterile phosphate-buffered saline, and randomized fragments of 1 to 2 mm 3 were transplanted subcutaneously by trocar in the flanks of syngeneic females that were either maintained in a virginal state or crossbred. Three to eight consecutive tumor passages were made in order to investigate their eventual progression to pregnancy independence. We have previously shown that PD tumors frequently arise as polyclonal populations, while their PI derivatives appear in subsequent transplant generations as monoclonal cell populations. In addition, the latter frequently display MMTV insertions undetected in the corresponding PD by Southern blot analysis (3).To evaluate the relevance of MMTV retroviral insertions for tumorigenesis with our model, we estimated the amount of exogenous MMTV provirus in mouse mammary gland and primary tumor DNA by quantitative PCR (qPCR) analysis. Genomic DNA was extracted as previously described (9), and amplifications were performed using viral strain-specific primers (10). Two-month-old virgin female mammary glands showed low provirus content, and in several cases, we were not able to detect the BALB/2 and BALB/14 MMTV variants.
R-spondin3 (RSPO3) is a member of a family of secreted proteins that enhance Wnt signaling pathways in diverse processes, including cancer. However, the role of RSPO3 in mammary gland and breast cancer development remains unclear. In this study, we show that RSPO3 is expressed in the basal stem cell-enriched compartment of normal mouse mammary glands but is absent from committed mature luminal cells in which exogenous RSPO3 impairs lactogenic differentiation. RSPO3 knockdown in basal-like mouse mammary tumor cells reduced canonical Wnt signaling, epithelial-to-mesenchymal transition-like features, migration capacity, and tumor formation Conversely, RSPO3 overexpression, which was associated with some LGR and RUNX factors, highly correlated with the basal-like subtype among patients with breast cancer. Thus, we identified RSPO3 as a novel key modulator of breast cancer development and a potential target for treatment of basal-like breast cancers. These findings identify RSPO3 as a potential therapetuic target in basal-like breast cancers. http://cancerres.aacrjournals.org/content/canres/78/16/4497/F1.large.jpg .
The progression of herpes simplex-2 genital infection in pregnant mice was studied by detection of viral antigens using immunoperoxidase in tissue sections, electron microscopy and virus isolation. The majority of mice (66.66%) died at 8-9 days post-inoculation. Abortions were observed in 69.23% of the infected mice along with impairment of labor and delivery. Herpes antigens were detected in most of the autonomic nerves of the uterus, including those surrounding small arterioles in the myometrium and the Auerbach and Meissner plexa of the large bowel, but not in the abortions or placentas. The infection of uterine autonomic fibers and myometrial cells could explain the delivery impairment and could have provoked a decrease in blood flow leading to abortions.
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