Loss of STAT1 from Mouse Mammary Epithelium Results in an Increased Neu-Induced Tumor Burden

Abstract

Type I and type II classes of interferons (IFNs) signal through the JAK/STAT1 pathway and are known to be important in adaptive and innate immune responses and in protection against tumors. Although STAT1 is widely considered a tumor suppressor, it remains unclear, however, if this function occurs in tumor cells (cell autonomous) or if STAT1 acts primarily through immune cells. Here, the question of whether STAT1 has a cell autonomous role in mammary tumor formation was addressed in a mouse model of ERBB2/neu-induced breast cancer in the absence and presence of STAT1. For this purpose, mice that carry floxed Stat1 alleles, which permit cell-specific removal of STAT1, were generated. To induce tumors only in mammary cells lacking STAT1, Stat1 floxed mice were crossed with transgenic mice that express cre recombinase and the neu oncogene under the mouse mammary tumor virus LTR (Stat1fl/fl NIC). Stat1 was effectively deleted in mammary epithelium of virgin Stat1fl/fl NIC females. Time-to-tumor onset was significantly shorter in Stat1fl/fl NIC females than in WT NIC (Wilcoxon rank sum test, P = .02). The median time-to-tumor onset in the Stat1fl/fl NIC mice was 49.4 weeks, whereas it was 62.4 weeks in the WT NIC mice. These results suggest that STAT1 in mammary epithelial cells may play a role in suppressing tumorigenesis. The Stat1 floxed allele described in this study is also a unique resource to determine the cellular targets of IFNs and STAT1 action, which should aid our understanding and appreciation of these pathways.

Initiation of Metastatic Breast Carcinoma by Targeting of the Ductal Epithelium with Adenovirus-Cre: A Novel Transgenic Mouse Model of Breast Cancer

“…Inducible genetic mutations driven by mammary specific promoters such as murine mammary tumor virus (MMTV) and whey acidic protein (WAP) have contributed a tremendous amount of knowledge about the genetic nature of breast cancer. However, the tissue specific expression of these promoters is compromised by their responsiveness to the endocrine system [10][11][12][13][14][15][16] , resulting in the variable expression of induced genetic mutations that do not mirror the expression of oncogenes typically overexpressed in human breast cancer. To overcome endocrine control of MMTV driven expression of oncogenes, Moody et al generated a conditional, doxycycline inducible model overexpressing Neu in the breast epithelium Our goal was to develop a mouse model of traceable breast cancer on a full C57BL/6 background that, after the permanent induction of mutational events, models the formation of a nascent tumor in the presence of immune pressure.…”

Janus Kinase 1 Is Essential for Inflammatory Cytokine Signaling and Mammary Gland Remodeling

“…The loss of the cytokine-mediated activation of STAT1 and STAT6 in the JAK1 conditional knockout mice seems to play a subordinate role that did not have any major impact on the development of the gland. It was previously reported that the expression and activation of STAT1 in the epithelium are dispensable for ductal elongation and alveologenesis (12), and recent work by Chen et al (44) suggested that optimal ductal branching morphogenesis depends on the presence of active STAT1 in the stroma. In contrast to STAT1-deficient females, STAT6 conventional knockout mice exhibited a delay in the development of alveolar cells during early pregnancy (19).…”

“…Five of the seven STAT proteins that are known in mammals (i.e., STAT1, STAT3, STAT5a, STAT5b, and STAT6) have been found to be sequentially activated at defined stages of mammary gland development (10,11). The levels of phosphorylated STAT1 have been reported to be elevated in nulliparous females, but this particular transcription factor seems to be largely dispensable for normal mammogenesis (12). A pregnancy-associated surge in circulating PRL results in a significant increase in the activation of both STAT5 proteins (i.e., STAT5a and STAT5b) as well as their downstream transcriptional targets, such as genes encoding milk proteins (13)(14)(15)(16).…”

Stat1 stimulates cap-independent mRNA translation to inhibit cell proliferation and promote survival in response to antitumor drugs

“…One mechanism depends on the induction of antitumor immune responses (6) and the other on the suppression of oncogenic signaling in a cell-autonomous (tumor cell-specific) manner (7)(8)(9)(10)(11). The antitumor properties of Stat1 have been best documented in breast cancers in which Stat1 assumes both immune regulatory and cell-autonomous functions to suppress either ErbB2/HER2 or estrogen receptor α (ERα)-mediated tumorigenesis (4,(10)(11)(12)(13)(14). Stat1 can also act as a promoter of mouse leukemogenesis caused by the activation of either Abelson murine leukemia viral oncogene homolog v-Abl or translocation-Ets-leukemia locus (TEL) and Janus kinase 2 fusion protein through immune regulatory mechanisms independent of IFN-γ (15).…”