Estradiol Promotes Growth and Angiogenesis in Polyoma Middle T Transgenic Mouse Mammary Tumor Explants

Dabrosin, Charlotta; Palmer, Kay; Muller, William J.; Gauldie, Jack

doi:10.1023/a:1022133219353

Cited by 52 publications

(52 citation statements)

References 17 publications

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“…injections of ketamine/xylazine, oophorectomised (OVX), and 3-mm pellets containing 17 b-oestradiol, 0.18 mg 60-d À1 release, or placebo pellets (Innovative Research of America, Sarasota, Florida, USA) were implanted subcutaneously in the animal's back 7 days before tumour induction. The pellets provide continuous release of oestradiol at serum concentrations of 150 -250 pM, confirmed previously by serum analysis (Dabrosin et al, 2003b), which is in the range of physiologic levels during the estrous cycle in mice. At 1 week after surgery, MCF-7 cells (5 Â 10 6 cells in 200 ml PBS) were injected s.c. on the right hind side flank.…”

Section: Animals and Oophorectomy Of Micesupporting

confidence: 64%

Effects of oestradiol and tamoxifen on VEGF, soluble VEGFR-1, and VEGFR-2 in breast cancer and endothelial cells

Garvin¹,

Nilsson²,

Dabrosin³

2005

Br J Cancer

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Angiogenesis is regulated by the balance between pro-and antiangiogenic factors. Vascular endothelial growth factor (VEGF), acting via the receptors VEGFR-1 and VEGFR-2, is a key mediator of tumour angiogenesis. The soluble form of the VEGF receptor-1 (sVEGFR-1) is an important negative regulator of VEGF-mediated angiogenesis. The majority of breast cancers are oestrogen dependent, but it is not fully understood how oestrogen and the antioestrogen, tamoxifen, affect the balance of angiogenic factors. Angiogenesis is a result of the interplay between cancer and endothelial cells, and sex steroids may exert effects on both cell types. In this study we show that oestradiol decreased secreted sVEGFR-1, increased secreted VEGF, and decreased the ratio of sVEGFR-1/ VEGF in MCF-7 human breast cancer cells. The addition of tamoxifen opposed these effects. Moreover, human umbilical vein endothelial cells (HUVEC) incubated with supernatants from oestradiol-treated MCF-7 cells exhibited higher VEGFR-2 levels than controls. In vivo, MCF-7 tumours from oestradiol þ tamoxifen-treated nude mice exhibited decreased tumour vasculature. Our results suggest that tamoxifen and oestradiol exert dual effects on the angiogenic environment in breast cancer by regulating cancer cell-secreted angiogenic ligands such as VEGF and sVEGFR-1 and by affecting VEGFR-2 expression of endothelial cells.

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Section: Animals and Oophorectomy Of Micesupporting

confidence: 64%

Effects of oestradiol and tamoxifen on VEGF, soluble VEGFR-1, and VEGFR-2 in breast cancer and endothelial cells

Garvin¹,

Nilsson²,

Dabrosin³

2005

Br J Cancer

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“…As shown by us, and others, these breast tumors express the ER during the early stage of cancer and decrease ER expression at later stages (29,30). Harvesting tumor tissue at early stages results in estrogen-dependent cancer growth in the syngeneic recipient mouse, as previously described (27,30). Tumors were established in oophorectomized mice with/without estrogen supplementation and with estrogen together with fulvestrant as described above.…”

Section: Murine Breast Cancer Modelsmentioning

confidence: 86%

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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“…However, other mechanisms may also contribute in the higher response of oestradiol treated tumours. We have recently shown that oestradiol-treated PyMT tumours used in this experiment have a higher microvessel count compared with tumours at the same size grown in OVX mice with placebo supplement (Dabrosin et al, 2003). This could affect the access of the tumour cells to the immune cells, that is, oestradiol-treated tumours have higher blood flow and are thereby more available to the immune system.…”

Section: Discussionmentioning

confidence: 86%

Section: Resultsmentioning

confidence: 99%

“…These tumours express the ER and E2 stimulates tumour cell proliferation in vitro and tumour growth in vivo (Dabrosin et al, 2003). Moreover, E2 enhances tumour angiogenesis in vivo (Dabrosin et al, 2003). The recombinant adenovirus vector expressing murine B7-1 and human IL-2 has previously been characterised and expression of both molecules have been confirmed (Emtage et al, 1998).…”

Section: Resultsmentioning

confidence: 99%

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Oestradiol enhances tumour regression induced by B7-1/IL-2 adenoviral gene transfer in a murine model of breast cancer

2003

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The majority of breast cancers are oestrogen dependent and although current treatment strategies have improved, approximately 50% of the patients will develop metastasis. New treatments that result in long-term systemic immunity are therefore being developed. We have previously shown that adenoviral gene transfer of B7-1/IL-2 to murine breast cancer induces a high rate of complete tumour regression and systemic immunity. Since oestrogens not only affect breast cancer but also have been shown to modulate immune function and secretion of immune-regulatory cytokines, we explored whether administration of oestradiol altered the immune response induced by an adenoviral vector expressing B7-1/IL-2. An oestrogen-dependent murine breast cancer tumour was used in ovariectomised mice, supplemented either oestradiol or placebo. We report the somewhat unexpected finding that intratumoral injection of adenovirus expressing B7-1/IL-2 induces complete tumour regression in 76% of oestradiol-supplemented mice, while only 18% of the tumours regressed in the oestrogen-depleted group. Cured mice in both groups exhibited a similar CTL response against the tumour antigen. However, intratumoral IFN-g levels, 2 days after B7-1/IL-2 injection, were significantly higher in mice treated with oestradiol compared to placebo. This may be one mechanism explaining the higher response rate of tumours in oestradiol-replenished mice.

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Estradiol Promotes Growth and Angiogenesis in Polyoma Middle T Transgenic Mouse Mammary Tumor Explants

Cited by 52 publications

References 17 publications

Effects of oestradiol and tamoxifen on VEGF, soluble VEGFR-1, and VEGFR-2 in breast cancer and endothelial cells

Effects of oestradiol and tamoxifen on VEGF, soluble VEGFR-1, and VEGFR-2 in breast cancer and endothelial cells

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

Oestradiol enhances tumour regression induced by B7-1/IL-2 adenoviral gene transfer in a murine model of breast cancer

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