Cholesterol and Cancer, in the Balance Sandrine Silvente-Poirot and Marc Poirot Science 343, 1445 (2014); DOI: 10.1126/science.1252787
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Updated information and services, including high-resolution figures, can be found in the online version of this article at: http://www.sciencemag.org/content/343/6178/1445.full.html A list of selected additional articles on the Science Web sites related to this article can be found at: http://www.sciencemag.org/content/343/6178/1445.full.html#related This article cites 15 articles, 5 of which can be accessed free: http://www.sciencemag.org/content/343/6178/1445.full.html#ref-list-1 This article appears in the following subject collections: Medicine, Diseases http://www.sciencemag.org/cgi/collection/medicine
Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2014 by the American Association for the Advancement of Science; all rights reserved. The title Science is a registered trademark of AAAS.
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PERSPECTIVES magnetic theory predicts that the local field enhancement in the junction of a plasmonic dimer increases monotonically with decreasing gap width. This property can be understood in a very simplified fashion as a “lightning rod” effect (see the figure, panel A). In the long wavelength regime, the nanoparticles are essentially equipotential; the potential drop from the electric component of the incident field across the dimer occurs only in the gap (4). For a dimer of length D with a gap of width dg, the local field enhancement will scale as D/dg and can be made very large by fabricating structures with large D and small dg. The large fields in the gap also result in a voltage drop between the nanoparticles that shifts the relative position of the Fermi energies εF of the nanoparticles (see the figure, panel B). In principle, these shifts allow electrons to transfer back and forth between the nanoparticles. This plasmon mode, referred to as the charge-transfer plasmon (CTP), coexists with the standard nonconductively coupled dimer plasmons but is distinct and appears at different frequencies because the local fields in the junctions are altered by the charge transport across the junction (5). For a vacuum junction, the tunneling matrix elements, which determine the transition rates of electrons between the two nanoparticles, decrease exponentially with increasing dg, and the CTP can only be observed for gaps a few angstroms in width. The creation of dimers with such narrow gaps is experimentally challenging but has recently been accomplished and has enabled the experimental observation of well-defined CTPs (6, 7). Theoretical calculations have predicted that if the nanoscale gap is filled by a conductive medium such as molecules, the tunneling transition matrix element will no longer exhibit an exponential dependence on dg and the CTP may be observed at larger dg (8, 9). The experimental verification of these predictions is a challenging task, but Tan et al. were able to nanofabricate dimers with extremely small gap widths, as well as assemble molecules that span the gap. By fabricating a silver nanocube dimer with very flat surfaces (see the figure, panel C), the junction area became large and uniform and could accommodate a sufficiently large number of conducting molecules. The CTP was observed for junction widths greater than 1 nm. These results not only allow quantum plasmonics to be studied with structures that have substantially larger gap widths than in previous experiments but also bridge two vibrant subfields of nanoscience, plasmonics, and
molecular electronics. Tan et al. show that the CTP depends on the type of molecule used, thus firmly establishing that its electronic properties are a key parameter in determining the optical frequency transport response of the nanoscale interparticle junction. Molecular tunnel junctions are normally characterizing with direct current (dc) or lowfrequency alternating current conductivity measurements. In the present experiment, the molecular conductance was probed instead at optical frequencies determined by the collective resonance of the plasmonic dimer. At high frequencies, additional intramolecular processes not present in dc transport, such as electron-electron and electron-vibrational scattering, could strongly influence molecular conductance. By exploiting the facile geometric tunability of plasmonic antennas, it should be possible to measure molecular
conductances at much higher frequencies. This experiment by Tan et al. also paves the way for novel device and molecular sensing applications. The conductance of a molecule can be switched or modulated, for example, by the application of an external dc field or by chemical reaction with another molecule. References 1. S. F. Tan et al., Science 343, 1496 (2014). 2. S. Lal et al., Chem. Soc. Rev. 37, 898 (2008). 3. J. A. Dieringer, R. B. Lettan 2nd, K. A. Scheidt, R. P. Van Duyne, J. Am. Chem. Soc. 129, 16249 (2007). 4. F. Le et al., ACS Nano 2, 707 (2008). 5. J. Zuloaga et al., Nano Lett. 9, 887 (2009). 6. K. J. Savage et al., Nature 491, 574 (2012). 7. J. A. Scholl, A. García-Etxarri, A. L. Koh, J. A. Dionne, Nano Lett. 13, 564 (2013). 8. O. Pérez-González et al., Nano Lett. 10, 3090 (2010). 9. P. Song, P. Nordlander, S. Gao, J. Chem. Phys. 134, 074701 (2011). 10.1126/science.1252245
CANCER
Cholesterol and Cancer, in the Balance Sandrine Silvente-Poirot and Marc Poirot Cholesterol metabolites can promote or suppress breast cancer, raising questions about how therapies might disrupt this balance.
M
ammalian cells synthesize cholesterol through a series of 21 enzymatic steps, generating numerous metabolites that are involved in the control of physiological and developmental processes. Cholesterol itself is the precursor of steroid hormones and sterols, the latter of which can be further modified into molecules that induce specific biological responses. Epidemiological studies have investigated the role of cholesterol in breast cancer risk, with contradictory findings. Recent studies, however, linking cholesterol metabolism to breast cancer may provide some insights. Certain cholesterol metabolites can promote (1, 2) or suppress (3) breast cancer. This raises the important question of how to regulate or inhibit the cholesterol metabolic pathway, and at which steps, in a therapeutic approach to cancer. Cholesterol is a unique lipid, essential for membrane biogenesis, cell proliferation, and cell differentiation (4). It is provided by the diet but is also mainly synthesized by the liver in humans and distributed throughout the UMR 1037 INSERM–University Toulouse III, Cancer Research Center of Toulouse, and Institut Claudius Regaud, 31052 Toulouse, France. E-mail: [email protected]; [email protected]
body via low-density lipoprotein (LDL) and high-density lipoprotein (HDL) transporters. Cancer has been associated with cholesterol, as it is the obligatory precursor of steroid hormones that are involved in tumor promotion (estrogens, androgens) as well as tumor death (glucocorticoids). Oncogenic processes enable cancer cells to synthesize their own cholesterol, which can be further metabolized to support their rapid proliferation. But contradictory results of epidemiologic studies make conclusions difficult regarding breast cancer. Thus, it is still not clear whether total cholesterol, HDL, or LDL can predict the occurrence of breast cancer. Many studies have investigated whether breast cancer risk is affected by blocking cholesterol synthesis with anticholesterol drugs such as statins, which inhibit the enzyme 3-hydroxy-3-methylglutaryl– coenzyme A reductase (HMG-CoA reductase or HMGCR). Here too, the findings are inconsistent. Statin use is associated with both an increased and decreased risk of breast cancer, and other studies report no association at all. A recent study has found that long-term (10 years) treatment with statins doubled the risk of invasive ductal
www.sciencemag.org SCIENCE VOL 343 28 MARCH 2014 Published by AAAS
1445
PERSPECTIVES
1446
Acetyl-CoA Inhibitors (statins)
Mevalonate
Lanosterol Inhibitors
Cholesterol Estrogen
Dendrogenin A
27HC
Other? Other?
Tumor promoters
Tumor suppressors
Cholesterol and breast cancer. Deregulations along the cholesterol metabolic pathway may favor the accumulation of metabolites with tumorpromoting activity (such as 27HC) but may also be detrimental to the formation of other metabolites that are beneficial to cell integrity and differentiation (such as dendrogenin A).
tion factor) P53, which are present in 50% of all cancers, increase the expression of several genes involved in the synthesis of sterols that are associated with the growth and invasiveness of breast cancer; this correlates with a low probability of breast cancer patient survival (10). Among these genes are those encoding 7-dehydrocholesterol reductase (catalyzes the production of cholesterol from 7-dehydrocholesterol), a subunit of cholesterol epoxide hydrolase (catalyzes the hydration of cholesterol-5,6-epoxides), and acyl– coenzyme A cholesterol acyltransferase 2 (catalyzes the esterification of cholesterol) (9, 10). These three enzymes have been characterized as therapeutic off-targets of tamoxifen in addition to the estrogen receptor (11). Inhibition of cholesterol biosynthesis at different post-lanosterol steps also has an impact on tumor growth, cell proliferation, and the induction of tumor cell differentiation (12). Depletion of enzymes that lead to the accumulation of sterols (specifically, the lack of sterol-C4-methyl oxidase and NADP-dependent steroid dehydrogenaselike enzymes results in the accumulation of 4-methylsterols) markedly sensitizes cancer cell lines and tumor xenografts to epidermal growth factor receptor–targeting drugs that are used to treat a number of cancers,
28 MARCH 2014 VOL 343
including breast cancer (13, 14). Inhibition of cholesterol epoxide hydrolase results in the accumulation of its cholesterol oxide substrates (cholesterol-5,6-epoxides), and this contributes to the antitumor and cell differentiation actions of tamoxifen in breast cancer cells (15). Yet another recent study reveals a cholesterol metabolite that suppresses breast cancer. Dendrogenin A is an amino-oxysterol metabolite that arises from cholesterol-5,6-epoxides and histamine in mammals (3). It triggers breast cancer cell redifferentation (recovery of normal physiological functions) both in vitro and in vivo and improves survival in animal models. Interestingly, the amount of this cholesterol metabolite decreased in tumors from breast cancer patients relative to normal matched tissues, suggesting a deregulation of dendrogenin A biosynthesis during carcinogenesis. Its properties and decreased presence in tumors suggest a physiological function in maintaining cell integrity and differentiation. It is not known whether the amounts of circulating cholesterol affect the biosynthesis of dendrogenin A, and the enzymes involved in its biosynthesis and catabolism are yet to be identified. Perhaps a balance in the production of tumor promoters such as 27HC and tumor suppressors such as dendrogenin A regulates breast tumor development (see the figure). Because other sterol derivatives may have such opposing properties, it is important to quantitatively profile sterols and oxysterols in the blood of patients, in tumor cells, and in cells of the tumor microenvironment, and also to measure the expression of genes and enzymes controlling the “sterolome.” This may lead to better targeting of these branches of the cholesterol metabolic pathways and to the development of new therapeutic approaches for breast cancer and possibly other cancers. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
E. R. Nelson et al., Science 342, 1094 (2013). Q. Wu et al., Cell Rep. 5, 637 (2013). P. de Medina et al., Nat. Commun. 4, 1840 (2013). S. Silvente-Poirot, M. Poirot, Curr. Opin. Pharmacol. 12, 673 (2012). J. A. McDougall et al., Cancer Epidemiol. Biomarkers Prev. 22, 1529 (2013). N. Alikhani et al., Oncogene 32, 961 (2013). J. Liu et al., Oncotarget 4, 1804 (2013). G. Llaverias et al., Am. J. Pathol. 178, 402 (2011). S. P. Pitroda et al., Proc. Natl. Acad. Sci. U.S.A. 106, 5837 (2009). W. A. Freed-Pastor et al., Cell 148, 244 (2012). M. Poirot et al., Curr. Opin. Pharmacol. 12, 683 (2012). M. A. Lasunción et al., Curr. Opin. Pharmacol. 12, 717 (2012). L. Gabitova et al., Clin. Cancer Res. 20, 28 (2014). A. Sukhanova et al., Cancer Discov. 3, 96 (2013). G. Segala et al., Biochem. Pharmacol. 86, 175 (2013).
SCIENCE www.sciencemag.org
Published by AAAS
10.1126/science.1252787
CREDIT: V. ALTOUNIAN/SCIENCE
carcinoma and invasive lobular carcinoma among postmenopausal women ( 5)—a disconcerting finding given that statins are commonly taken for chronic, long-term use. Investigations at the laboratory level have revealed a more complex map of the influence of cholesterol metabolism on the promotion or suppression of breast cancer that could account for these conflicting studies. Hypercholesterolemia was shown to promote mammary tumor growth and invasiveness in several mouse transgenic models (6–8), which suggested that cholesterol or its metabolites promote breast cancer. Indeed, recent studies show that the cholesterol metabolite 27-hydroxycholesterol (27HC) spurs tumor growth by interacting with the estrogen receptor in several animal models of breast cancer (1, 2). 27HC also promotes breast cancer metastasis by interacting with liver X receptor, a transcription factor (1). These observations seem to have clinical relevance because increased amounts of the enzyme that eliminates 27HC [called oxysterol and steroid 7-alpha-hydroxylase (CYP7B1)] in human breast cancer samples were associated with improved patient survival (1, 2), and increased amounts of the enzyme that converts cholesterol to 27HC [called sterol 27-hydroxylase (CYP27A1)] were observed in more aggressive mammary tumors. Tumor samples (that express the estrogen receptor) from breast cancer patients showed a higher content of 27HC compared to normal breast tissue in the patients and relative to the same tissues in cancer-free controls. This shows that there is a deregulation of 27HC production during carcinogenesis toward a higher production of the metabolite; this increase is independent of the amount of circulating cholesterol (2). Blocking 27HC production, using an inhibitor of CYP27A1 or a statin, attenuated hypercholesterolemia-promoted tumor growth in a mouse model (1). These studies highlight that a cholesterol metabolite is a tumor promoter in breast cancer (in the presence of the estrogen receptor). The deregulation of metabolite production at different points in the cholesterol biosynthesis pathway has been reported to promote breast cancer or cause resistance to therapies in different in vitro and in vivo models. Thus, mucin1, a glycoprotein that is aberrantly overexpressed in numerous cancers, induces a lipid and sterol metabolism transcriptional signature in breast cancer tissue that is predictive of resistance to tamoxifen treatment, the gold standard for therapy and prevention of estrogen receptor–expressing breast cancer (9). Similarly, mutant forms of the tumor suppressor protein (and transcrip-
This copy is for your personal, non-commercial use only.
If you wish to distribute this article to others, you can order high-quality copies for your colleagues, clients, or customers by clicking here. Permission to republish or repurpose articles or portions of articles can be obtained by following the guidelines here.
Updated information and services, including high-resolution figures, can be found in the online version of this article at: http://www.sciencemag.org/content/343/6178/1445.full.html A list of selected additional articles on the Science Web sites related to this article can be found at: http://www.sciencemag.org/content/343/6178/1445.full.html#related This article cites 15 articles, 5 of which can be accessed free: http://www.sciencemag.org/content/343/6178/1445.full.html#ref-list-1 This article appears in the following subject collections: Medicine, Diseases http://www.sciencemag.org/cgi/collection/medicine
Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2014 by the American Association for the Advancement of Science; all rights reserved. The title Science is a registered trademark of AAAS.
Downloaded from www.sciencemag.org on April 2, 2014
The following resources related to this article are available online at www.sciencemag.org (this information is current as of April 2, 2014 ):
PERSPECTIVES magnetic theory predicts that the local field enhancement in the junction of a plasmonic dimer increases monotonically with decreasing gap width. This property can be understood in a very simplified fashion as a “lightning rod” effect (see the figure, panel A). In the long wavelength regime, the nanoparticles are essentially equipotential; the potential drop from the electric component of the incident field across the dimer occurs only in the gap (4). For a dimer of length D with a gap of width dg, the local field enhancement will scale as D/dg and can be made very large by fabricating structures with large D and small dg. The large fields in the gap also result in a voltage drop between the nanoparticles that shifts the relative position of the Fermi energies εF of the nanoparticles (see the figure, panel B). In principle, these shifts allow electrons to transfer back and forth between the nanoparticles. This plasmon mode, referred to as the charge-transfer plasmon (CTP), coexists with the standard nonconductively coupled dimer plasmons but is distinct and appears at different frequencies because the local fields in the junctions are altered by the charge transport across the junction (5). For a vacuum junction, the tunneling matrix elements, which determine the transition rates of electrons between the two nanoparticles, decrease exponentially with increasing dg, and the CTP can only be observed for gaps a few angstroms in width. The creation of dimers with such narrow gaps is experimentally challenging but has recently been accomplished and has enabled the experimental observation of well-defined CTPs (6, 7). Theoretical calculations have predicted that if the nanoscale gap is filled by a conductive medium such as molecules, the tunneling transition matrix element will no longer exhibit an exponential dependence on dg and the CTP may be observed at larger dg (8, 9). The experimental verification of these predictions is a challenging task, but Tan et al. were able to nanofabricate dimers with extremely small gap widths, as well as assemble molecules that span the gap. By fabricating a silver nanocube dimer with very flat surfaces (see the figure, panel C), the junction area became large and uniform and could accommodate a sufficiently large number of conducting molecules. The CTP was observed for junction widths greater than 1 nm. These results not only allow quantum plasmonics to be studied with structures that have substantially larger gap widths than in previous experiments but also bridge two vibrant subfields of nanoscience, plasmonics, and
molecular electronics. Tan et al. show that the CTP depends on the type of molecule used, thus firmly establishing that its electronic properties are a key parameter in determining the optical frequency transport response of the nanoscale interparticle junction. Molecular tunnel junctions are normally characterizing with direct current (dc) or lowfrequency alternating current conductivity measurements. In the present experiment, the molecular conductance was probed instead at optical frequencies determined by the collective resonance of the plasmonic dimer. At high frequencies, additional intramolecular processes not present in dc transport, such as electron-electron and electron-vibrational scattering, could strongly influence molecular conductance. By exploiting the facile geometric tunability of plasmonic antennas, it should be possible to measure molecular
conductances at much higher frequencies. This experiment by Tan et al. also paves the way for novel device and molecular sensing applications. The conductance of a molecule can be switched or modulated, for example, by the application of an external dc field or by chemical reaction with another molecule. References 1. S. F. Tan et al., Science 343, 1496 (2014). 2. S. Lal et al., Chem. Soc. Rev. 37, 898 (2008). 3. J. A. Dieringer, R. B. Lettan 2nd, K. A. Scheidt, R. P. Van Duyne, J. Am. Chem. Soc. 129, 16249 (2007). 4. F. Le et al., ACS Nano 2, 707 (2008). 5. J. Zuloaga et al., Nano Lett. 9, 887 (2009). 6. K. J. Savage et al., Nature 491, 574 (2012). 7. J. A. Scholl, A. García-Etxarri, A. L. Koh, J. A. Dionne, Nano Lett. 13, 564 (2013). 8. O. Pérez-González et al., Nano Lett. 10, 3090 (2010). 9. P. Song, P. Nordlander, S. Gao, J. Chem. Phys. 134, 074701 (2011). 10.1126/science.1252245
CANCER
Cholesterol and Cancer, in the Balance Sandrine Silvente-Poirot and Marc Poirot Cholesterol metabolites can promote or suppress breast cancer, raising questions about how therapies might disrupt this balance.
M
ammalian cells synthesize cholesterol through a series of 21 enzymatic steps, generating numerous metabolites that are involved in the control of physiological and developmental processes. Cholesterol itself is the precursor of steroid hormones and sterols, the latter of which can be further modified into molecules that induce specific biological responses. Epidemiological studies have investigated the role of cholesterol in breast cancer risk, with contradictory findings. Recent studies, however, linking cholesterol metabolism to breast cancer may provide some insights. Certain cholesterol metabolites can promote (1, 2) or suppress (3) breast cancer. This raises the important question of how to regulate or inhibit the cholesterol metabolic pathway, and at which steps, in a therapeutic approach to cancer. Cholesterol is a unique lipid, essential for membrane biogenesis, cell proliferation, and cell differentiation (4). It is provided by the diet but is also mainly synthesized by the liver in humans and distributed throughout the UMR 1037 INSERM–University Toulouse III, Cancer Research Center of Toulouse, and Institut Claudius Regaud, 31052 Toulouse, France. E-mail: [email protected]; [email protected]
body via low-density lipoprotein (LDL) and high-density lipoprotein (HDL) transporters. Cancer has been associated with cholesterol, as it is the obligatory precursor of steroid hormones that are involved in tumor promotion (estrogens, androgens) as well as tumor death (glucocorticoids). Oncogenic processes enable cancer cells to synthesize their own cholesterol, which can be further metabolized to support their rapid proliferation. But contradictory results of epidemiologic studies make conclusions difficult regarding breast cancer. Thus, it is still not clear whether total cholesterol, HDL, or LDL can predict the occurrence of breast cancer. Many studies have investigated whether breast cancer risk is affected by blocking cholesterol synthesis with anticholesterol drugs such as statins, which inhibit the enzyme 3-hydroxy-3-methylglutaryl– coenzyme A reductase (HMG-CoA reductase or HMGCR). Here too, the findings are inconsistent. Statin use is associated with both an increased and decreased risk of breast cancer, and other studies report no association at all. A recent study has found that long-term (10 years) treatment with statins doubled the risk of invasive ductal
www.sciencemag.org SCIENCE VOL 343 28 MARCH 2014 Published by AAAS
1445
PERSPECTIVES
1446
Acetyl-CoA Inhibitors (statins)
Mevalonate
Lanosterol Inhibitors
Cholesterol Estrogen
Dendrogenin A
27HC
Other? Other?
Tumor promoters
Tumor suppressors
Cholesterol and breast cancer. Deregulations along the cholesterol metabolic pathway may favor the accumulation of metabolites with tumorpromoting activity (such as 27HC) but may also be detrimental to the formation of other metabolites that are beneficial to cell integrity and differentiation (such as dendrogenin A).
tion factor) P53, which are present in 50% of all cancers, increase the expression of several genes involved in the synthesis of sterols that are associated with the growth and invasiveness of breast cancer; this correlates with a low probability of breast cancer patient survival (10). Among these genes are those encoding 7-dehydrocholesterol reductase (catalyzes the production of cholesterol from 7-dehydrocholesterol), a subunit of cholesterol epoxide hydrolase (catalyzes the hydration of cholesterol-5,6-epoxides), and acyl– coenzyme A cholesterol acyltransferase 2 (catalyzes the esterification of cholesterol) (9, 10). These three enzymes have been characterized as therapeutic off-targets of tamoxifen in addition to the estrogen receptor (11). Inhibition of cholesterol biosynthesis at different post-lanosterol steps also has an impact on tumor growth, cell proliferation, and the induction of tumor cell differentiation (12). Depletion of enzymes that lead to the accumulation of sterols (specifically, the lack of sterol-C4-methyl oxidase and NADP-dependent steroid dehydrogenaselike enzymes results in the accumulation of 4-methylsterols) markedly sensitizes cancer cell lines and tumor xenografts to epidermal growth factor receptor–targeting drugs that are used to treat a number of cancers,
28 MARCH 2014 VOL 343
including breast cancer (13, 14). Inhibition of cholesterol epoxide hydrolase results in the accumulation of its cholesterol oxide substrates (cholesterol-5,6-epoxides), and this contributes to the antitumor and cell differentiation actions of tamoxifen in breast cancer cells (15). Yet another recent study reveals a cholesterol metabolite that suppresses breast cancer. Dendrogenin A is an amino-oxysterol metabolite that arises from cholesterol-5,6-epoxides and histamine in mammals (3). It triggers breast cancer cell redifferentation (recovery of normal physiological functions) both in vitro and in vivo and improves survival in animal models. Interestingly, the amount of this cholesterol metabolite decreased in tumors from breast cancer patients relative to normal matched tissues, suggesting a deregulation of dendrogenin A biosynthesis during carcinogenesis. Its properties and decreased presence in tumors suggest a physiological function in maintaining cell integrity and differentiation. It is not known whether the amounts of circulating cholesterol affect the biosynthesis of dendrogenin A, and the enzymes involved in its biosynthesis and catabolism are yet to be identified. Perhaps a balance in the production of tumor promoters such as 27HC and tumor suppressors such as dendrogenin A regulates breast tumor development (see the figure). Because other sterol derivatives may have such opposing properties, it is important to quantitatively profile sterols and oxysterols in the blood of patients, in tumor cells, and in cells of the tumor microenvironment, and also to measure the expression of genes and enzymes controlling the “sterolome.” This may lead to better targeting of these branches of the cholesterol metabolic pathways and to the development of new therapeutic approaches for breast cancer and possibly other cancers. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
E. R. Nelson et al., Science 342, 1094 (2013). Q. Wu et al., Cell Rep. 5, 637 (2013). P. de Medina et al., Nat. Commun. 4, 1840 (2013). S. Silvente-Poirot, M. Poirot, Curr. Opin. Pharmacol. 12, 673 (2012). J. A. McDougall et al., Cancer Epidemiol. Biomarkers Prev. 22, 1529 (2013). N. Alikhani et al., Oncogene 32, 961 (2013). J. Liu et al., Oncotarget 4, 1804 (2013). G. Llaverias et al., Am. J. Pathol. 178, 402 (2011). S. P. Pitroda et al., Proc. Natl. Acad. Sci. U.S.A. 106, 5837 (2009). W. A. Freed-Pastor et al., Cell 148, 244 (2012). M. Poirot et al., Curr. Opin. Pharmacol. 12, 683 (2012). M. A. Lasunción et al., Curr. Opin. Pharmacol. 12, 717 (2012). L. Gabitova et al., Clin. Cancer Res. 20, 28 (2014). A. Sukhanova et al., Cancer Discov. 3, 96 (2013). G. Segala et al., Biochem. Pharmacol. 86, 175 (2013).
SCIENCE www.sciencemag.org
Published by AAAS
10.1126/science.1252787
CREDIT: V. ALTOUNIAN/SCIENCE
carcinoma and invasive lobular carcinoma among postmenopausal women ( 5)—a disconcerting finding given that statins are commonly taken for chronic, long-term use. Investigations at the laboratory level have revealed a more complex map of the influence of cholesterol metabolism on the promotion or suppression of breast cancer that could account for these conflicting studies. Hypercholesterolemia was shown to promote mammary tumor growth and invasiveness in several mouse transgenic models (6–8), which suggested that cholesterol or its metabolites promote breast cancer. Indeed, recent studies show that the cholesterol metabolite 27-hydroxycholesterol (27HC) spurs tumor growth by interacting with the estrogen receptor in several animal models of breast cancer (1, 2). 27HC also promotes breast cancer metastasis by interacting with liver X receptor, a transcription factor (1). These observations seem to have clinical relevance because increased amounts of the enzyme that eliminates 27HC [called oxysterol and steroid 7-alpha-hydroxylase (CYP7B1)] in human breast cancer samples were associated with improved patient survival (1, 2), and increased amounts of the enzyme that converts cholesterol to 27HC [called sterol 27-hydroxylase (CYP27A1)] were observed in more aggressive mammary tumors. Tumor samples (that express the estrogen receptor) from breast cancer patients showed a higher content of 27HC compared to normal breast tissue in the patients and relative to the same tissues in cancer-free controls. This shows that there is a deregulation of 27HC production during carcinogenesis toward a higher production of the metabolite; this increase is independent of the amount of circulating cholesterol (2). Blocking 27HC production, using an inhibitor of CYP27A1 or a statin, attenuated hypercholesterolemia-promoted tumor growth in a mouse model (1). These studies highlight that a cholesterol metabolite is a tumor promoter in breast cancer (in the presence of the estrogen receptor). The deregulation of metabolite production at different points in the cholesterol biosynthesis pathway has been reported to promote breast cancer or cause resistance to therapies in different in vitro and in vivo models. Thus, mucin1, a glycoprotein that is aberrantly overexpressed in numerous cancers, induces a lipid and sterol metabolism transcriptional signature in breast cancer tissue that is predictive of resistance to tamoxifen treatment, the gold standard for therapy and prevention of estrogen receptor–expressing breast cancer (9). Similarly, mutant forms of the tumor suppressor protein (and transcrip-
