Tamoxifen, Flaxseed, and the Lignan Enterolactone Increase Stroma- and Cancer Cell–Derived IL-1Ra and Decrease Tumor Angiogenesis in Estrogen-Dependent Breast Cancer

Lindahl, Gabriel; Saarinen, Niina M.; Abrahamsson, Annelie; Dabrosin, Charlotta

doi:10.1158/0008-5472.can-10-2289

Cited by 71 publications

(63 citation statements)

References 42 publications

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“…We have previously found an association of estrogen levels and the in vivo levels of several inflammatory biomarkers in human breast tissue. 4,5,7,9,11,34 In these studies, both pre-and post-menopausal women and patients investigated before and after anti-estrogen treatment were included, thus reflecting cohorts of women with a wide range of hormone levels, whereas in the present study, postmenopausal women exhibiting minor variation of estradiol levels were included. Hence, correlations with estrogen may not be expected in this selected population.…”

Section: E1229723-4mentioning

confidence: 99%

“…We have previously shown increased extracellular in vivo levels of several inflammatory mediators, such as interleukin (IL)-1, IL-8, chemokine (C-C motif) ligand (CCL) 2, CCL5, leptin, and vascular endothelial growth factor (VEGF) in breast cancers of women and an association with sex steroids of these factors in normal human breast tissue. [4][5][6][7][8][9][10][11][12] Mammographic density has been associated with increased risk of breast cancer. 13 In a meta-analysis women with >75% dense breast area have a 4-fold increased risk of developing breast cancer compared to women with <5% dense breast area.…”

Section: Introductionmentioning

confidence: 99%

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Dense breast tissue in postmenopausal women is associated with a pro-inflammatory microenvironment in vivo

et al. 2016

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Inflammation is one of the hallmarks of carcinogenesis. High mammographic density has been associated with increased risk of breast cancer but the mechanisms behind are poorly understood. We evaluated whether breasts with different mammographic densities exhibited differences in the inflammatory microenvironment.Postmenopausal women attending the mammography-screening program were assessed having extreme dense, n D 20, or entirely fatty breasts (nondense), n D 19, on their regular mammograms. Thereafter, the women were invited for magnetic resonance imaging (MRI), microdialysis for the collection of extracellular molecules in situ and a core tissue biopsy for research purposes. On the MRI, lean tissue fraction (LTF) was calculated for a continuous measurement of breast density. LTF confirmed the selection from the mammograms and gave a continuous measurement of breast density. Microdialysis revealed significantly increased extracellular in vivo levels of IL-6, IL-8, vascular endothelial growth factor, and CCL5 in dense breast tissue as compared with nondense breasts. Moreover, the ratio IL-1Ra/IL-1b was decreased in dense breasts. No differences were found in levels of IL1b, IL-1Ra, CCL2, leptin, adiponectin, or leptin:adiponectin ratio between the two breast tissue types. Significant positive correlations between LTF and the pro-inflammatory cytokines as well as between the cytokines were detected. Stainings of the core biopsies exhibited increased levels of immune cells in dense breast tissue.Our data show that dense breast tissue in postmenopausal women is associated with a pro-inflammatory microenvironment and, if confirmed in a larger cohort, suggests novel targets for prevention therapies for women with dense breast tissue.

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Section: E1229723-4mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dense breast tissue in postmenopausal women is associated with a pro-inflammatory microenvironment in vivo

et al. 2016

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“…Several types of immune cells express the ER, and estrogen affects the expression of inflammatory mediators in neutrophils and macrophages (8,9). We have shown that estrogen increases the influx of macrophages into breast cancers and induces a protumorigenic phenotype (M2) in these cells (10).…”

Section: Introductionmentioning

confidence: 99%

Estradiol Promotes Breast Cancer Cell Migration via Recruitment and Activation of Neutrophils

Rodriguez

Abrahamsson

Jensen

et al. 2017

Cancer Immunology Research

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Estradiol (E 2 ) plays a key role in breast cancer progression. Most breast cancer recurrences express the estrogen receptor (ER), but nearly 50% of patients are resistant to antiestrogen therapy. Novel therapeutic targets of ER-positive breast cancers are needed. Protumoral neutrophils expressing the lymphocyte functionassociated antigen 1 (LFA-1) integrin may mediate cancer metastasis, and TGFb1 is the major chemoattractant for neutrophils. The role of E 2 in neutrophil-ER þ breast cancer cell interactions is unknown. We studied this in vivo using murine breast cancers in immunocompetent mice and human breast cancers in nude mice. Cell dissemination was evaluated in a zebrafish model, and microdialysis of breast cancer patients was performed. In vitro studies were done with mammosphere cultures of breast cancer cells and human neutrophils. We found that E 2 increased the number of LFA-1 þ neutrophils recruited to the invasive edge of mouse tumors, increased TGFb1 secretion and promoted neutrophil infiltration in mammospheres, and induced overexpression of LFA-1 in neutrophils. In zebrafish, in the presence of E 2 , neutrophils increased dissemination of ER þ breast cancer cells via LFA-1 and TGFb1, thus causing noninvasive cancer cells to be highly metastatic. Time-lapse imaging in zebrafish revealed close interactions of neutrophils with cancer cells, which drove breast cancer metastasis. We also found that extracellular TGFb1 was overproduced in human breast cancer tissue compared with adjacent normal breast tissue. Thus, E 2 can regulate immune/cancer cell interactions in tumor microenvironments. Our results indicate that extracellular TGFb1 is a relevant target in human breast cancer.

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“…Our group previously reported the release of IL-1s from both cancer and stromal cells in a xenograft nude mouse model, and an alteration of IL-1 levels after tamoxifen or diet modification by flaxseed and lignan enterolactone, but not by genistein (237). In Paper I of this thesis, we therefore intended first to determine the presence of IL-1 cytokines in the extracellular space of human breast tissue in vivo, and to investigate the role of sex steroids in the regulation of IL-1 cytokines in normal human breast tissue.…”

Section: Resultsmentioning

confidence: 95%

Hormonal regulation of immune modulators in human breast tissue

Morad¹

2015

Linköping University Medical Dissertations

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Breast cancer is the most common form of cancer and the second leading cause of malignancy-associated death in women worldwide. Estrogens are the main sex hormones in women. They are essential for the development and function of normal breast mammary glands; however, prolonged exposure to estrogens increases the risk of breast cancer development and progression. Approximately two-thirds of all breast cancer patients are positive for estrogen receptor (ER), but only 50% of those cases can benefit from antiestrogen therapy. In this thesis we investigated the effects of estrogen, diet modification, and anti-estrogen drugs on several immune modulators in normal human breast tissue. We used the microdialysis technique to sample the immune modulators in situ in normal human breast tissue, in malignant breast tissue, and in tumor tissue from both the immune competent mice with murine breast cancer and immune deficient mice bearing human breast tumors. Furthermore, we also used ex vivo culture of normal breast tissue and in vitro cell culture of breast cancer cell lines. A combined cell culture (co-culture) of breast cancer cell lines, together with the primary mature adipocytes, was also used in this thesis. In Paper I and Paper II, our results suggested that estrogen exerted both proinflammatory and pro-tumorigenic effects in normal human breast tissue. Estradiol increased extracellular interleukin-1β (IL-1β) and leptin levels and decreased IL-1Ra and adiponectin levels in normal human breast tissue. In contrast, tamoxifen decreased IL-1β and leptin levels and increased IL-1Ra and adiponectin levels, shifting the environment towards an antiinflammatory and antitumorigenic state. Diet modification with flaxseed for 30 days also increased IL-1Ra levels, creating an anti-inflammatory environment in normal breast tissue. In the breast cancer tissue, we found that extracellular IL-1β levels and leptin levels were significantly higher, whereas adiponectin levels were significantly lower, compared with normal adjacent breast tissue, which suggested a more proinflammatory state. In the third paper, our in vivo investigation of normal breast tissue revealed significant correlations between vascular endothelial growth factor (VEGF) and leptin, IL-1β and leptin, and between VEGF and IL-1β. No correlations were found in the abdominal subcutaneous (s.c.) fat tissue. Our in vitro inhibition experiments suggested that VEGF was a potent regulator of leptin, but that leptin was not a potent regulator of VEGF. Co-culture per se altered the release of VEGF and leptin and enhanced the effects of estradiol, compared with monocultures of the included cell types. In conclusion, the results presented in this thesis will increase the overall understanding of the role of estrogens in breast cancer, which may be useful in future treatment studies

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Tamoxifen, Flaxseed, and the Lignan Enterolactone Increase Stroma- and Cancer Cell–Derived IL-1Ra and Decrease Tumor Angiogenesis in Estrogen-Dependent Breast Cancer

Cited by 71 publications

References 42 publications

Dense breast tissue in postmenopausal women is associated with a pro-inflammatory microenvironment in vivo

Dense breast tissue in postmenopausal women is associated with a pro-inflammatory microenvironment in vivo

Estradiol Promotes Breast Cancer Cell Migration via Recruitment and Activation of Neutrophils

Hormonal regulation of immune modulators in human breast tissue

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