The Role of Steroid Hormones on the Regulation of Vascular Endothelial Growth Factorm
2002; Elsevier BV; Volume: 161; Issue: 1 Linguagem: Inglês
10.1016/s0002-9440(10)64186-7
ISSN1525-2191
Autores Tópico(s)Breast Cancer Treatment Studies
ResumoI read with interest the recent correspondence between Soares et al and Iruela-Arispa and Graubert1Soares R Reis-Filho JS Gartner F Schmitt FC Iruela-Arispa L Graubert MD Vascular endothelial growth factor, transforming growth factor-α, and estrogen receptors: possible cross-talks and interactions.Am J Pathol. 2002; 160: 381-383Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar on regulation of vascular endothelial growth factor (VEGF) by steroid hormones in uterine and breast cancer cells. Since VEGF is a very potent angiogenic growth factor and a potential molecular target for steroid receptor-based anti-hormone therapy, it is important to understand the role of steroid hormone receptors in the regulation of this gene. However, current studies in the literature remain controversial with regard to the role of steroid hormones on regulation of the VEGF gene. Our group has analyzed VEGF expression by steroid hormones in breast and uterine cells over the past 10 years, and we have published some results that differ with those presented by the authors of the letters.1Soares R Reis-Filho JS Gartner F Schmitt FC Iruela-Arispa L Graubert MD Vascular endothelial growth factor, transforming growth factor-α, and estrogen receptors: possible cross-talks and interactions.Am J Pathol. 2002; 160: 381-383Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar I would like to add a few comments to those already proposed in the letters, and propose some reasons for discrepancies in the literature related to the role of steroid hormones and VEGF regulation. In addition, I would like to briefly comment on the role of progesterone, and synthetic progestins in the regulation of VEGF, especially since recent evidence links the use of estrogen/progestin combination hormone replacement therapy with higher incidence of breast cancer than the use of estrogen alone.2Schairer C Lubin J Troisi R Sturgeon S Brinton L Hoover R Estrogen-progestin replacement and risk of breast cancer.JAMA. 2000; 284: 691-694Crossref PubMed Google Scholar, 3Ross RK Paganini-Hill A Wan PC Pike MC Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin.J Natl Cancer Inst. 2000; 92: 328-332Crossref PubMed Scopus (809) Google Scholar The role of progesterone in regulating angiogenic growth factors is just beginning to emerge, and may have a role in the progression of tumor following hormone administration. Soares et al describe in their unpublished results that VEGF mRNA is "overexpressed" by estradiol in MCF-7 breast cancer cells.1Soares R Reis-Filho JS Gartner F Schmitt FC Iruela-Arispa L Graubert MD Vascular endothelial growth factor, transforming growth factor-α, and estrogen receptors: possible cross-talks and interactions.Am J Pathol. 2002; 160: 381-383Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar Similar to results of Soares et al,1Soares R Reis-Filho JS Gartner F Schmitt FC Iruela-Arispa L Graubert MD Vascular endothelial growth factor, transforming growth factor-α, and estrogen receptors: possible cross-talks and interactions.Am J Pathol. 2002; 160: 381-383Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar a 4- to 6-fold induction of VEGF by estrogen is reported in the MCF-7 cells by other investigators.4Ruohola JK Valve EM Karkkainen MJ Joukov V Alitalo K Harkonen PL Vascular endothelial growth factors are differentially regulated by steroid hormones and anti-estrogens in breast cancer cells.Mol Cell Endocrinol. 1999; 149: 29-40Crossref PubMed Scopus (220) Google Scholar Furthermore, unlike the "overexpressed" or modest induction of VEGF by estrogens reported in breast cancer cells,1Soares R Reis-Filho JS Gartner F Schmitt FC Iruela-Arispa L Graubert MD Vascular endothelial growth factor, transforming growth factor-α, and estrogen receptors: possible cross-talks and interactions.Am J Pathol. 2002; 160: 381-383Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 4Ruohola JK Valve EM Karkkainen MJ Joukov V Alitalo K Harkonen PL Vascular endothelial growth factors are differentially regulated by steroid hormones and anti-estrogens in breast cancer cells.Mol Cell Endocrinol. 1999; 149: 29-40Crossref PubMed Scopus (220) Google Scholar we and others 5Hyder SM Murthy L Stancel GM Progestin regulation of vascular endothelial growth factor in human breast cancer.Cancer Res. 1998; 58: 392-395PubMed Google Scholar, 6Bermonta L Lamielle-Musarda F Chezya E Weisz A Adessi GL 17-Estradiol inhibits forskolin-induced vascular endothelial growth factor promoter in MCF-7 breast adenocarcinoma cells.J Steroid Biochem Mol Biol. 2001; 78: 343-349Crossref PubMed Scopus (8) Google Scholar, 7Bogin L Degani H Hormonal regulation of VEGF in orthotopic MCF-7 human breast cancer.Cancer Res. 2002; 62: 1948-1951PubMed Google Scholar and our unpublished observations) have not been able to demonstrate estrogen induction of VEGF in estrogen receptor (ER)-positive MCF-7, T47-D, or ZR-75 breast cancer cells at either mRNA level (measured at 3 to 6 and 24 hours after estrogen exposure), or protein level (enzyme-linked immunosorbent assay after 18 hours, to measure secretory forms of VEGF in media). Most genes under direct regulation by estradiol are up-regulated in this time frame even in vivo, including VEGF in the uterus.8Hyder SM Chiappetta C Stancel GM The synthetic estrogen 17 a-ethinyl estradiol induces a similar pattern of uterine gene expression as the endogenous estrogen 17 b-estradiol.J Pharmacol Exp Ther. 1999; 290: 740-747PubMed Google Scholar Thus, although we and others have described estrogen response elements in the regulatory regions of the VEGF gene,9Hyder SM Nawaz Z Chiappetta C Stancel GM Identification of functional estrogen response elements in the gene coding for the potent angiogenic factor vascular endothelial growth factor.Cancer Res. 2000; 60: 3183-3190PubMed Google Scholar, 10Mueller MD Vigne JL Minchenko A Lebovic DI Leitman DC Taylor RN Regulation of vascular endothelial growth factor (VEGF) gene transcription by estrogen receptors α and β.Proc Natl Acad Sci USA. 2000; 97: 10972-10977Crossref PubMed Scopus (305) Google Scholar the data in the literature clearly indicates that estrogen induction of VEGF is cell type-dependent and factors other than ER are also involved in the estrogen response. Fluctuation of such factors in cell lines in different laboratories could explain some discrepancies between the results of various investigators using similar experimental conditions. Identification of such additional factors may be important to fully understand the role of estrogen in VEGF response, and may even provide new prognostic factors for endocrine responsive tumors. In one respect, the results of Soares et al1Soares R Reis-Filho JS Gartner F Schmitt FC Iruela-Arispa L Graubert MD Vascular endothelial growth factor, transforming growth factor-α, and estrogen receptors: possible cross-talks and interactions.Am J Pathol. 2002; 160: 381-383Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar may be very important, and potentially may be describing an indirect effect of estrogen on VEGF regulation that they observe after 48 hours. Therefore, it is important that more details about their experimental conditions be made available to understand the importance of such an observation. At present, without evidence for use of anti-hormones to block VEGF induction, the best we can do is to conclude (as Soares et al have done) that the results of Soares et al with MCF-7 cells describe an indirect effect of E on VEGF production. With respect to the effects of estrogen on VEGF expression in the uterus, our results, and those of others, differ considerably from the results reported by Iruela-Arispa in human uterus.1Soares R Reis-Filho JS Gartner F Schmitt FC Iruela-Arispa L Graubert MD Vascular endothelial growth factor, transforming growth factor-α, and estrogen receptors: possible cross-talks and interactions.Am J Pathol. 2002; 160: 381-383Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar While Iruela-Arispa describe a modest induction (1.6-fold) of this growth factor in human uterine cells in response to estrogen,1Soares R Reis-Filho JS Gartner F Schmitt FC Iruela-Arispa L Graubert MD Vascular endothelial growth factor, transforming growth factor-α, and estrogen receptors: possible cross-talks and interactions.Am J Pathol. 2002; 160: 381-383Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar we and others have seen substantial induction of mRNA for this growth factor in the rat uterus.11Hyder SM Stancel GM Chiappetta C Murthy L Boettger-Tong HL Makela S Uterine expression of vascular endothelial growth factor is increased by estradiol as well as tamoxifen.Cancer Res. 1996; 56: 3954-3960PubMed Google Scholar, 12Cullinan-Bove K Koos RD Vascular endothelial growth factor/vascular permeability factor expression in the rat uterus: rapid stimulation by estrogen correlates with estrogen-induced increases in uterine capillary permeability and growth.Endocrinology. 1993; 133: 829-837Crossref PubMed Scopus (369) Google Scholar Unlike the conclusions reached by Iruela-Arispa on the role of ER in VEGF induction, there is considerable evidence that, in rat uterine cells, ER is one of the components controlling estrogen-induced VEGF production.11Hyder SM Stancel GM Chiappetta C Murthy L Boettger-Tong HL Makela S Uterine expression of vascular endothelial growth factor is increased by estradiol as well as tamoxifen.Cancer Res. 1996; 56: 3954-3960PubMed Google Scholar, 13Charnock-Jones DS Sharkey AM Rajput-Williams J Burch D Schofield JP Fountain SA Boocock CA Smith SK Identification and localization of alternately spliced mRNAs for vascular endothelial growth factor in human uterus and estrogen regulation in endometrial carcinoma cell lines.Biol Reprod. 1993; 48: 1120-1128Crossref PubMed Scopus (427) Google Scholar It is surprising that, while all uterine cell types contain ER, only the stromal cells respond to estrogen for VEGF induction.11Hyder SM Stancel GM Chiappetta C Murthy L Boettger-Tong HL Makela S Uterine expression of vascular endothelial growth factor is increased by estradiol as well as tamoxifen.Cancer Res. 1996; 56: 3954-3960PubMed Google Scholar, 14Ma W Tan J Matsumoto H Robert B Abrahamson DR Das SK Dey SK Adult tissue angiogenesis: evidence for negative regulation by estrogen in the uterus.Mol Endocrinol. 2001; 15: 1983-1992Crossref PubMed Scopus (96) Google Scholar This suggests that, like the cell-specific effects of estrogen on VEGF regulation in the breast, additional factors are also required for ER-dependent induction of VEGF in the various cell types of the uterus. To complicate the matters even more, some investigators have found negative regulation of VEGF by estrogen in uterine and breast tumor cell lines.7Bogin L Degani H Hormonal regulation of VEGF in orthotopic MCF-7 human breast cancer.Cancer Res. 2002; 62: 1948-1951PubMed Google Scholar, 15Stoner M Wang F Wormke M Nguyen T Samudio I Vyhlidal C Marme D Finkenzeller G Safe S Inhibition of vascular endothelial growth factor expression in HEC1A endometrial cancer cells through interactions of estrogen receptor α and Sp3 proteins.J Biol Chem. 2000; 275: 22769-22779Crossref PubMed Scopus (78) Google Scholar It must be stressed that while the conflicting results of VEGF regulation by estrogens is mostly derived in vitro from tumor cells, where the expression of co-factors may vary tremendously, the evidence from normal uterine cells is derived from intact uterus where fluctuation in any co-factors may have been minimized.11Hyder SM Stancel GM Chiappetta C Murthy L Boettger-Tong HL Makela S Uterine expression of vascular endothelial growth factor is increased by estradiol as well as tamoxifen.Cancer Res. 1996; 56: 3954-3960PubMed Google Scholar, 13Charnock-Jones DS Sharkey AM Rajput-Williams J Burch D Schofield JP Fountain SA Boocock CA Smith SK Identification and localization of alternately spliced mRNAs for vascular endothelial growth factor in human uterus and estrogen regulation in endometrial carcinoma cell lines.Biol Reprod. 1993; 48: 1120-1128Crossref PubMed Scopus (427) Google Scholar The presence of such co-factors may also be species-dependent leading to some of the variability reported with respect to sex steroid control of VEGF expression. We cannot rule out that there may even be different degrees of mRNA stabilization in various tissues leading to much higher levels of VEGF message being observed in response to estrogen administration in certain cases. Iruela-Arispa suggest that VEGF may not be regulated by estrogens in the human uterus because the estrogen levels are low during the first 5 days following menstruation.1Soares R Reis-Filho JS Gartner F Schmitt FC Iruela-Arispa L Graubert MD Vascular endothelial growth factor, transforming growth factor-α, and estrogen receptors: possible cross-talks and interactions.Am J Pathol. 2002; 160: 381-383Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar However, we have determined that in the rat uterus, unlike many other estrogen-responsive genes, VEGF is exquisitely sensitive to low levels of estrogen and potentially could be up-regulated at very low concentrations.8Hyder SM Chiappetta C Stancel GM The synthetic estrogen 17 a-ethinyl estradiol induces a similar pattern of uterine gene expression as the endogenous estrogen 17 b-estradiol.J Pharmacol Exp Ther. 1999; 290: 740-747PubMed Google Scholar While admittedly speculative, expression of VEGF may be supersensitive to estrogens and respond to low levels of hormones immediately following menstruation. This remains to be proven but should be considered for future studies. An important point that was briefly raised in the letters by Soares et al and Iruela-Arispa and Graubert1Soares R Reis-Filho JS Gartner F Schmitt FC Iruela-Arispa L Graubert MD Vascular endothelial growth factor, transforming growth factor-α, and estrogen receptors: possible cross-talks and interactions.Am J Pathol. 2002; 160: 381-383Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar is the role of progesterone in VEGF regulation. The role of progesterone in the regulation of VEGF has not been well addressed. A limited number of studies show that VEGF is under progestin regulation in both uterine and in a subset of breast cancer cells.5Hyder SM Murthy L Stancel GM Progestin regulation of vascular endothelial growth factor in human breast cancer.Cancer Res. 1998; 58: 392-395PubMed Google Scholar, 12Cullinan-Bove K Koos RD Vascular endothelial growth factor/vascular permeability factor expression in the rat uterus: rapid stimulation by estrogen correlates with estrogen-induced increases in uterine capillary permeability and growth.Endocrinology. 1993; 133: 829-837Crossref PubMed Scopus (369) Google Scholar, 16Hyder SM Chiappetta C Stancel GM Pharmacological and endogenous progestins induce vascular endothelial growth factor expression in human breast cancer cells.Int J Cancer. 2001; 92: 469-473Crossref PubMed Scopus (80) Google Scholar It seems that progesterone induction of VEGF is also under strict cell type control.5Hyder SM Murthy L Stancel GM Progestin regulation of vascular endothelial growth factor in human breast cancer.Cancer Res. 1998; 58: 392-395PubMed Google Scholar We have determined that VEGF is under progestin regulation in T47-D cells,5Hyder SM Murthy L Stancel GM Progestin regulation of vascular endothelial growth factor in human breast cancer.Cancer Res. 1998; 58: 392-395PubMed Google Scholar and similar induction can be seen at both the message and protein level in BT-474 cells, but not in MCF-7 cells or in ZR-75 cells (our unpublished observation). This induction was not seen even after priming MCF-7 or ZR-75 cell with estrogen (10–9 mol/L for 48 hours) to up-regulate progestin response (our unpublished observations). Clearly, progesterone control of VEGF also seems to follow the same trend as estrogen control of VEGF, ie, it is cell type-dependent, and perhaps the progesterone responsive cells have either gained or lost a function that is important in order for them to respond to the hormone. This would be particularly insidious in occult tumors where progesterone may be able to drive the production of VEGF in selected cells, giving them a growth advantage over others, and leading to tumor expansion. In conclusion, VEGF induction by steroid hormones appears to be tissue and cell type-dependent. Most evidence suggests that ER is required for estrogen response but that the receptor by itself is not sufficient. Similarly, progestin response seems to depend on progesterone receptor but the receptor does not seem to be sufficient for such an induction either. It is now important to further analyze the effects of hormones on expression of VEGF in vivo in different cells and tissues to gain a better understanding of the role of sex steroid hormones on VEGF regulation. While some data on uterine cells is available in this respect,11Hyder SM Stancel GM Chiappetta C Murthy L Boettger-Tong HL Makela S Uterine expression of vascular endothelial growth factor is increased by estradiol as well as tamoxifen.Cancer Res. 1996; 56: 3954-3960PubMed Google Scholar, 12Cullinan-Bove K Koos RD Vascular endothelial growth factor/vascular permeability factor expression in the rat uterus: rapid stimulation by estrogen correlates with estrogen-induced increases in uterine capillary permeability and growth.Endocrinology. 1993; 133: 829-837Crossref PubMed Scopus (369) Google Scholar, 14Ma W Tan J Matsumoto H Robert B Abrahamson DR Das SK Dey SK Adult tissue angiogenesis: evidence for negative regulation by estrogen in the uterus.Mol Endocrinol. 2001; 15: 1983-1992Crossref PubMed Scopus (96) Google Scholar data in different cells of the mammary gland is lacking. Studies need to be performed to identify biological importance of VEGF during tissue development, and to determine whether there is any heterogeneity within the mammary cells for hormone responsiveness with respect to VEGF induction. It is possible that not all mammary gland cells express VEGF in response to hormonal stimulation, and this may also be reflected in the fact that only selected mammary tumor cells respond to estrogen or progesterone in vitro. The need for in vivo data is important to understand the role of hormone-induced VEGF in progression of neoplastic disease to target anti-VEGF treatment effectively. I thank the Editor-in-Chief for the opportunity to add a few comments to the important points mentioned regarding the influence of hormones on VEGF expression by Soares et al and Iruela-Arista and Graubert,1Soares R Reis-Filho JS Gartner F Schmitt FC Iruela-Arispa L Graubert MD Vascular endothelial growth factor, transforming growth factor-α, and estrogen receptors: possible cross-talks and interactions.Am J Pathol. 2002; 160: 381-383Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar and the National Institutes of Health (CA-86916; HD-08615) and the Susan G. Komen Breast Cancer Foundation for supporting our studies on VEGF regulation.
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