Estrogen Decreases Chemokine Levels in Murine Mammary Tissue: Implications for the Regulatory Role of MIP-1 Alpha and MCP-1/JE in Mammary Tumor Formation

Fanti, Peter; Nazareth, Michael R.; Bucelli, Robert C.; Mineo, Michael; Gibbs, Kathleen; Kumin, M.; Grzybek, K.; Raiber, Lisa; Poppenberg, Kristin; Janis, Kelly; Schwach, Catherine; Aronica, Susan M.

doi:10.1385/endo:22:2:161

Cited by 17 publications

(12 citation statements)

References 32 publications

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“…The best ER-sensitive splicing event was found in FANCA, which is regulated by steroid hormone (51). Two other ER-sensitive ASEs were found in MCL-1 and CCL4 that are tamoxifen and estrogen target genes, respectively (52,53). Notably, it was recently shown that estrogen, ER, and its coregulators can affect the alternative splicing of their target genes (54).…”

Section: Discussionmentioning

confidence: 99%

Identification of Alternative Splicing Markers for Breast Cancer

Venables

Klinck²,

Bramard³

et al. 2008

Cancer Research

174

154

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Breast cancer is the most common cause of cancer death among women under age 50 years, so it is imperative to identify molecular markers to improve diagnosis and prognosis of this disease. Here, we present a new approach for the identification of breast cancer markers that does not measure gene expression but instead uses the ratio of alternatively spliced mRNAs as its indicator. Using a high-throughput reverse transcription-PCR-based system for splicing annotation, we monitored the alternative splicing profiles of 600 cancer-associated genes in a panel of 21 normal and 26 cancerous breast tissues. We validated 41 alternative splicing events that significantly differed in breast tumors relative to normal breast tissues. Most cancer-specific changes in splicing that disrupt known protein domains support an increase in cell proliferation or survival consistent with a functional role for alternative splicing in cancer. In a blind screen, a classifier based on the 12 best cancer-associated splicing events correctly identified cancer tissues with 96% accuracy. Moreover, a subset of these alternative splicing events could order tissues according to histopathologic grade, and 5 markers were validated in a further blind set of 19 grade 1 and 19 grade 3 tumor samples. These results provide a simple alternative for the classification of normal and cancerous breast tumor tissues and underscore the putative role of alternative splicing in the biology of cancer. [Cancer Res 2008;68(22):9525-31]

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Section: Discussionmentioning

confidence: 99%

Identification of Alternative Splicing Markers for Breast Cancer

Venables

Klinck²,

Bramard³

et al. 2008

Cancer Research

174

154

View full text Add to dashboard Cite

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“…Another potential mechanism affecting both T cells and APC is the homing of T cells to lymph nodes and APC from the FRT to the draining lymph nodes. Estradiol reduces expression of chemokine receptors CCR2 and CXCR3, as well as reducing migratory activity in response to MIP-1␣ and MCP-1 (59).…”

Section: Discussionmentioning

confidence: 99%

“…Estrogen has pleiotropic effects, especially on cells of the immune system, and it can inhibit B cell development (54 -56), induce thymic atrophy (57), reduce developing T cell populations (58), induce monocyte apoptosis (59), and inhibit DC differentiation (60). Estrogens increase the production of biologically active TGF␤ from uterine epithelial and vaginal cells, and anti-TGF␤ Abs ablate the estradiol-induced suppression of Ag presentation by rat vaginal cells to CD4 ϩ T cells (34,61).…”

Section: Discussionmentioning

confidence: 99%

Paternal Antigen-Bearing Cells Transferred during Insemination Do Not Stimulate Anti-Paternal CD8+ T Cells: Role of Estradiol in Locally Inhibiting CD8+ T Cell Responses

Seavey

Mosmann

2006

The Journal of Immunology

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Maternal immunological tolerance of the semiallogeneic fetus involves several overlapping mechanisms to balance maternal immunity and fetal development. Anti-paternal CD8+ T cells are suppressed during pregnancy in some but not all mouse models. Since semen has been shown to mediate immune modulation, we tested whether exposure to paternal Ag during insemination activated or tolerized anti-paternal CD8+ T cells. The uterine lumen of mated female mice contained male MHC I+ cells that stimulated effector, but not naive, CD8+ T cells ex vivo. Maternal MHC class I+ myeloid cells fluxed into the uterine lumen in response to mating and cross-presented male H-Y Ag to effector, but not naive, CD8+ T cells ex vivo. However, neither unprimed nor previously primed TCR-transgenic CD8+ T cells specific for either paternal MHC I or H-Y Ag proliferated in vivo after mating. These T cells subsequently responded normally to i.p. challenge, implicating ignorance rather than anergy as the main reason for the lack of response. CD8+ T cells responded to either peptide Ag or male cells delivered intravaginally in ovariectomized mice, but this response was inhibited by systemic estradiol (inducing an estrus-like state). Subcutaneous Ag induced responses in both cases. Allogeneic dendritic cells did not induce responses intravaginally even in ovariectomized mice in the absence of estradiol. These results suggest that inhibition of antiallogeneic responses is restricted both locally to the reproductive tract and temporally to the estrous phase of the menstrual cycle, potentially decreasing the risk of maternal immunization against paternal Ags during insemination.

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“…However, estrogen reduces the levels of MCP-1 in human coronary artery endothelial cells (HCAECs) (86). Estrogen significantly increased the levels of some specific chemokines such as MIP-1a and MCP-1/JE in mammary cells in vivo and in vitro (87), while the expression of chemokines MCP-1/JE and MIP-1a did not change in murine monocytes co-cultured with estrogen or tamoxifen (88). A study has found that both estrogen and tamoxifen significantly down-regulate the expression of CCR2 by murine monocytes and that they downregulate the expression of CXCR3 by murine monocytes to a lesser extent at the same time (88).…”

Section: Chemokinesmentioning

confidence: 99%

“…Treatment with estrogen or raloxifene and tamoxifen was ineffective at changing levels of MCP-1 expression in human umbilical vein endothelial cells (HUVECs) (86). In cultured mammary cells and murine mammary tissue, estrogen significantly down-regulates the levels of specific chemokines -MIP-1a and MCP-1/ JE -compared to baseline levels, and estrogen also suppresses expression of JE/monocyte chemoattractant protein 1(MCP-1/JE) mRNA in murine macrophage cells (87). A study by Janis et al reported no change in the expression of the chemokines MCP-1/JE and MIP-1a in murine monocytes, regardless of whether those cells were co-cultured with estrogen or tamoxifen (88).…”

Section: The Mechanism By Which Estrogen Modulates Chemokinesmentioning

confidence: 99%