Tamoxifen induction of angiogenic factor expression in endometrium

Hague, Stephen J.; Manek, Sanjiv; Oehler, Martin K.; MacKenzie, I.Z.; Bicknell, Roy; Rees, Margaret

doi:10.1038/sj.bjc.6600157

Cited by 24 publications

(13 citation statements)

References 41 publications

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“…These observations suggest that estrogen indeed stimulates angiogenesis and thus tumor stromal growth, but that tamoxifen does not block those functions of the ER necessary for bone marrow cell recruitment and angiogenesis. Consistent with this notion, previous reports have indicated that tamoxifen does not inhibit the proangiogenic effects of estrogen in the uterus (49,50).…”

Section: Discussionsupporting

confidence: 74%

Systemic Stromal Effects of Estrogen Promote the Growth of Estrogen Receptor–Negative Cancers

Gupta

Proia²,

Cingöz³

et al. 2007

Cancer Research

155

146

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Numerous hormonal factors contribute to the lifetime risk of breast cancer development. These include inherited genetic mutations, age of menarche, age of menopause, and parity. Inexplicably, there is evidence indicating that ovariectomy prevents the formation of both estrogen receptor (ER)-positive and ER-negative breast cancers, suggesting that ERnegative breast cancers are dependent on ovarian hormones for their formation. To examine the mechanism(s) by which this may be occurring, we investigated the hypothesis that steroid hormones promote the outgrowth of ER-negative cancers by influencing host cell types distinct from the mammary epithelial cells. We used a novel xenograft mouse model of parturition-induced breast carcinoma formation, in which the tumors that arise following pregnancy lack the expression of nuclear hormone receptors, thereby recapitulating many clinical cases of this disease. Despite lacking ER expression, the tumors arising following pregnancy in this model require circulating estrogens for their formation. Moreover, increasing the levels of circulating estrogens sufficed to promote the formation and progression of ERnegative cancers, which was accompanied by a systemic increase in host angiogenesis and was attendant with the recruitment of bone marrow-derived stromal cells. Furthermore, bone marrow cells from estrogen-treated mice were sufficient to promote tumor growth. These results reveal a novel mechanism by which estrogens promote the growth of ER-negative cancers. [Cancer Res 2007;67(5):2062-71]

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Section: Discussionsupporting

confidence: 74%

Systemic Stromal Effects of Estrogen Promote the Growth of Estrogen Receptor–Negative Cancers

Gupta

Proia²,

Cingöz³

et al. 2007

Cancer Research

155

146

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“…We were the ®rst to show that ADM is an angiogenic factor (Zhao et al, 1998). Furthermore we demonstrated that ADM expression in uterine leiomyomas (benign smooth muscle tumours) correlated with vascular density (Hague et al, 2000). In addition, we reported the presence of ADM in human endometrium where it was upregulated by the nonsteroidal antiestrogen tamoxifen (TAM) (Zhao et al, 1998).…”

Section: Introductionmentioning

confidence: 80%

Adrenomedullin inhibits hypoxic cell death by upregulation of Bcl-2 in endometrial cancer cells: a possible promotion mechanism for tumour growth

et al. 2001

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Regions of hypoxia are a common feature of solid tumours. When tumour cells are exposed to hypoxic stress, transcription of a battery of genes is initiated. The angiogenic factor adrenomedullin (ADM) is a hypoxia regulated gene. ADM is thought to act through the G protein-coupled receptor calcitonin receptor-like receptor (CRLR), with speci®city being conferred by the receptor associated modifying protein 2 (RAMP2). Here we report for the ®rst time that ADM treated or stably transfected Ishikawa cells overexpressing ADM show increased resistance to hypoxia induced apoptosis. These cells also show an upregulation of the oncoprotein Bcl-2, which is protective against hypoxic cell death when transiently transfected into Ishikawa cells. Since Ishikawa cells express the putative ADM-receptor CRLR ± RAMP2 the production and secretion of ADM with the consecutive upregulation of Bcl-2 could establish an autocrine/ paracrine mechanism rescuing malignant cells from hypoxic cell death. These results, taken together with our previous ®ndings that ADM is an angiogenic factor which is upregulated by the nonsteroidal antiestrogen tamoxifen (TAM) in endometrial cells, implicate this peptide as a promoter of tumour growth and a possible target for anticancer strategies. Oncogene (2001) 20, 2937 ± 2945.

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“…Moreover, treatment with rPEDF restored the angiogenic balance by resisting tamoxifen-induced uterine VEGF elevation, as seen by the decrease of both uterine weight and CD34-marked blood vessels. Former evidence characterizing the changes in uterine vasculature after tamoxifen treatment in postmenopausal patients was not persistent, possibly due to limited sample size and increased heterogeneity (28,29).…”

Section: Discussionmentioning

confidence: 99%

Pigment Epithelium–Derived Factor Alleviates Tamoxifen-Induced Endometrial Hyperplasia

Goldberg

Bar‐Joseph

Grossman

et al. 2015

Molecular Cancer Therapeutics

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Tamoxifen is a cornerstone component of adjuvant endocrine therapy for patients with hormone-receptor-positive breast cancer. Its significant adverse effects include uterine hyperplasia, polyps, and increased risk of endometrial cancer. However, the underlying molecular mechanism remains unclear. Excessive angiogenesis, a hallmark of tumorigenesis, is a result of disrupted balance between pro-and anti-angiogenic factors. VEGF is a proangiogenic factor shown to be elevated by tamoxifen in the uterus. Pigment epithelium-derived factor (PEDF) is a potent anti-angiogenic factor that suppresses strong pro-angiogenic factors, such as VEGF. Our aim was to investigate whether angiogenic balance plays a role in tamoxifen-induced uterine pathologies, elucidate the molecular impairment in that network, and explore potential intervention to offset the proposed imbalance elicited by tamoxifen. Using in vivo mouse models, we demonstrated that tamoxifen induced a dose-dependent shift in endogenous uterine angiogenic balance favoring VEGF over PEDF. Treatment with recombinant PEDF (rPEDF) abrogated tamoxifen-induced uterine hyperplasia and VEGF elevation, resulting in reduction of blood vessels density. Exploring the molecular mechanism revealed that tamoxifen promoted survival and malignant transformation pathways, whereas rPEDF treatment prevents these changes. Activation of survival pathways was decreased, demonstrated by reduction in AKT phosphorylation concomitant with elevation in JNK phosphorylation. Estrogen receptor-a and c-Myc oncoprotein levels were reduced. Our findings provide novel insight into the molecular mechanisms tamoxifen induces in the uterus, which may become the precursor events of subsequent endometrial hyperplasia and cancer. We demonstrate that rPEDF may serve as a useful intervention to alleviate the risk of tamoxifen-induced endometrial pathologies.

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Tamoxifen induction of angiogenic factor expression in endometrium

Cited by 24 publications

References 41 publications

Systemic Stromal Effects of Estrogen Promote the Growth of Estrogen Receptor–Negative Cancers

Systemic Stromal Effects of Estrogen Promote the Growth of Estrogen Receptor–Negative Cancers

Adrenomedullin inhibits hypoxic cell death by upregulation of Bcl-2 in endometrial cancer cells: a possible promotion mechanism for tumour growth

Pigment Epithelium–Derived Factor Alleviates Tamoxifen-Induced Endometrial Hyperplasia

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