HER-2/neu Status Is a Determinant of Mammary Aromatase Activity <i>In vivo</i>: Evidence for a Cyclooxygenase-2-Dependent Mechanism

Subbaramaiah, Kotha; Howe, Louise R.; Port, Elisa; Brogi, Edi; Fishman, Jack; Liu, Catherine H.; Hla, Timothy; Hudis, Clifford A.; Dannenberg, Andrew J.

doi:10.1158/0008-5472.can-05-4076

Cited by 86 publications

(89 citation statements)

References 46 publications

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“…3 H]androstenedione (5,9,18,44,45). The reaction was also done in the presence of letrozole, a specific aromatase inhibitor, as well as a specificity control and without NADPH as a background control.…”

Section: Methodsmentioning

confidence: 99%

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Hsp90 and PKM2 Drive the Expression of Aromatase in Li-Fraumeni Syndrome Breast Adipose Stromal Cells

Subbaramaiah

Brown

Zahid

et al. 2016

Journal of Biological Chemistry

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Li-Fraumeni syndrome (LFS) patients harbor germ line mutations in the TP53 gene and are at increased risk of hormone receptor-positive breast cancers. Recently, elevated levels of aromatase, the rate-limiting enzyme for estrogen biosynthesis, were found in the breast tissue of LFS patients. Although p53 down-regulates aromatase expression, the underlying mechanisms are incompletely understood. In the present study, we found that LFS stromal cells expressed higher levels of Hsp90 ATPase activity and aromatase compared with wild-type stromal cells. Inhibition of Hsp90 ATPase suppressed aromatase expression. Silencing Aha1 (activator of Hsp90 ATPase 1), a cochaperone of Hsp90 required for its ATPase activity, led to both inhibition of Hsp90 ATPase activity and reduced aromatase expression. In comparison with wild-type stromal cells, increased levels of the Hsp90 client proteins, HIF-1␣, and PKM2 were found in LFS stromal cells. A complex comprised of HIF-1␣ and PKM2 was recruited to the aromatase promoter II in LFS stromal cells. Silencing either HIF-1␣ or PKM2 suppressed aromatase expression in LFS stromal cells. CP-31398, a p53 rescue compound, suppressed levels of Aha1, Hsp90 ATPase activity, levels of PKM2 and HIF-1␣, and aromatase expression in LFS stromal cells. Consistent with these in vitro findings, levels of Hsp90 ATPase activity, Aha1, HIF-1␣, PKM2, and aromatase were increased in the mammary glands of p53 null versus wild-type mice. PKM2 and HIF-1␣ were shown to co-localize in the nucleus of stromal cells of LFS breast tissue. Taken together, our results show that the Aha1-Hsp90-PKM2/ HIF-1␣ axis mediates the induction of aromatase in LFS.Estrogen is an important mediator in the development and progression of breast cancer. Cytochrome P450 aromatase, a product of the CYP19A1 gene, catalyzes the synthesis of estrogens from androgens (1). In postmenopausal women, the adipose tissue becomes the main site of estrogen biosynthesis, and particularly, the breast adipose tissue is considered an important source of estrogens that drive the growth of hormone-dependent breast cancers. Consequently, it is important to elucidate the mechanisms that regulate the transcription of the CYP19A1 gene. The expression of aromatase is tightly regulated, with transcription being under the control of several distinct tissue-selective promoters (2-4). In normal breast adipose tissue, aromatase is expressed at low levels under the control of promoter I.4, whereas in obesity and cancer, the coordinated activation of the proximal promoters I.3 and promoter II (PII) 3 causes a significant increase in aromatase expression (3-5). The proximal promoters I.3 and PII are located close to each other, activated by stimulation of the cAMP 3 PKA 3 cAMP response element-binding protein (CREB) pathway (6, 7), and aided by many other regulators including CREB-regulated transcription co-activator 2 (CRTC2), p300, and hypoxia-inducible factor-1␣ (HIF-1␣) (8 -11).Several cytokines and tumor promoters, including prostaglandin E 2 , tumor necrosis ...

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Section: Methodsmentioning

confidence: 99%

“…In addition, its expression is regulated by oncogenes such as HER-2/neu and tumor suppressor genes including BRCA1, LKB1, and p53 (9,11,(13)(14)(15)(16)(17)(18). Germ line mutations in the TP53 gene, which encodes p53, lead to Li-Fraumeni Syndrome (LFS).…”

mentioning

confidence: 99%

Hsp90 and PKM2 Drive the Expression of Aromatase in Li-Fraumeni Syndrome Breast Adipose Stromal Cells

Subbaramaiah

Brown

Zahid

et al. 2016

Journal of Biological Chemistry

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“…Aromatase, PGT, BRCA1, PR, aP2, b-actin, and 18S rRNA probes were labeled with [ 32 P]CTP by random priming. The blots were probed as described previously (14).…”

Section: Northern Blottingmentioning

confidence: 99%

“…Positive correlations have been detected between COX and aromatase expression in human breast cancer specimens (11)(12)(13). In mice that express a mammary-targeted COX-2 transgene, increased PGE 2 and aromatase levels were observed (14). Silencing of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the key enzyme responsible for inactivating PGE 2 upregulated aromatase (15).…”

Section: Introductionmentioning

confidence: 99%

The Prostaglandin Transporter Regulates Adipogenesis and Aromatase Transcription

Subbaramaiah

Hudis

Dannenberg

2011

Cancer Prevention Research

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Cytochrome P450 aromatase, encoded by the CYP19 gene, catalyzes estrogen synthesis. In obese postmenopausal women, increased estrogen synthesis in adipose tissue has been linked to hormonedependent breast carcinogenesis. Hence, it is important to elucidate the mechanisms that regulate CYP19 gene expression. Prostaglandin E 2 (PGE 2 ) stimulates the cyclic AMP (cAMP) ! protein kinase A (PKA) ! cAMP responsive element binding protein (CREB) pathway leading to increased CYP19 transcription. The prostaglandin transporter (PGT) removes PGE 2 from the extracellular milieu and delivers it to the cytosol, where it is inactivated. The main objective of this study was to determine whether PGT regulates CYP19 transcription. Silencing of PGT in preadipocytes increased PGE 2 levels in the extracellular medium, thereby stimulating the cAMP ! PKA pathway resulting in enhanced interaction between pCREB, p300, and the CYP19 I.3/II promoter. A reciprocal decrease in the interaction between the CYP19 I.3/II promoter and BRCA1, a repressor of CYP19 transcription, was observed. Overexpressing PGT reduced extracellular PGE 2 levels, suppressed the cAMP ! PKA pathway, enhanced the interaction between BRCA1 and p300, and inhibited aromatase expression. We also compared the PGT ! aromatase axis in preadipocytes versus adipocytes. Aromatase levels were markedly increased in preadipocytes versus adipocytes. This increase in aromatase was explained, at least in part, by reduced PGT levels leading to enhanced PGE 2 ! cAMP ! PKA signaling. In addition to regulating aromatase expression, PGT-mediated changes in extracellular PGE 2 levels were a determinant of adipocyte differentiation. Collectively, these results suggest that PGT modulates adipogenesis and thereby PGE 2 -mediated activation of the cAMP ! PKA ! CREB pathway leading to altered CYP19 transcription and aromatase activity.

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“…Il a également été montré qu'il existe une corrélation entre l'expression de COX2 et du REα dans des carcinomes mammaires ductaux (Barisik et al, 2010). Une surexpression de COX2 induirait une augmentation de l'expression et de l'activité de l'aromatase in vivo dans des tissus mammaires (Subbaramaiah et al, 2006 ;Muller-Decker et al, 2005). L'augmentation de la synthèse locale d'estrogènes par la COX2 contribuerait à la croissance cellulaire médiée par le REα et au maintien d'un environnement inflammatoire par l'expression de la PGES.…”

Section: L'effet Protecteur De L'e2 Chez Des Souris Présentant Une Enunclassified

The DHEA metabolite 7β-hydroxy-epiandrosterone exerts anti-estrogenic effects on breast cancer cell lines

et al. 2012

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Titre : La 7β-hydroxy-épiandrostérone dans des modèles in vitro de cancer du sein : effets anti-estrogéniques et rôle des récepteurs des estrogènes. La 7β-hydroxy-épiandrostérone, stéroïde endogène dérivant de la DHEA, présente des propriétés antiinflammatoires. En effet, elle module la voie des prostaglandines (PGs) en inhibant la production de la PGE2 pro-inflammatoires et en augmentant la production de la 15-Deoxy-∆ 12,14 -PGJ2 cyto-protectrice in vivo et in vitro. Les faibles doses de 7β-hydroxy-épiandrostérone (1nM, 10nM, 100nM) pour lesquelles ces effets sont observés, suggèrent une liaison à un récepteur spécifique. L'inflammation et la production des PGs jouent un rôle important dans le développement et la prolifération des tumeurs mammaires estrogéno-dépendantes. Le 17β-estradiol (E2), en se fixant sur les récepteurs des estrogènes (REs), induit la production de PGE2 et la prolifération cellulaire dans ces cellules tumorales. De ce fait, notre objectif était de tester les effets de la 7β-hydroxy-épiandrostérone sur la prolifération (comptage avec exclusion au bleu trypan), le cycle cellulaire et l'apoptose (cytométrie de flux) dans les lignées cellulaires de cancer du sein MCF-7 (REα+, REβ+, GPR30+) et MDA-MB-231 (REα-, REβ+, GPR30+) et d'identifier une(des) cible(s) potentielle(s) dans ces cellules (transactivation) et dans des cellules négatives pour les REs nucléaires SKBr3 (GPR30+) (études de prolifération). Cette étude a montré que la 7β-hydroxy-épiandrostérone exerce des effets anti-estrogéniques dans les cellules MCF-7 et MDA-MB-231 associés à une inhibition de la prolifération et un arrêt du cycle cellulaire. Les études de transactivation et de prolifération avec les agonistes spécifiques des REs ont montré une interaction avec le REβ. De plus, les résultats des études de proliférations sur les trois lignées cellulaires suggèrent que la 7β-hydroxy-épiandrostérone pourrait également interagir avec le GPR30. Ces résultats indiquent que ce stéroïde androgène agit comme un anti-estrogène. De plus, c'est la première fois qu'un stéroïde androgène à faible dose montre une action anti-proliférative dans des lignées de cancers du sein. De études ultérieures restent à réaliser afin de mieux comprendre ces effets observés. Mots clés : 7β-hydroxy-épiandrostérone, récepteurs des estrogènes, lignées de carcinomes mammaires, prolifération, transactivationThe DHEA metabolite 7β-hydroxy-epiandrosterone exerts anti-estrogenic effects on breast cancer cell lines 7β-hydroxy-epiandrosterone, an endogenous androgenic derivative of DHEA, has previously been shown to exert anti-inflammatory action in vitro and in vivo via a shift from prostaglandin E2 (PGE2) to 15-deoxy-∆ 12,14 -PGJ2 production. This modulation in prostaglandin production was obtained with low concentrations of 7β-hydroxy-epiandrosterone (1-100 nM) and suggested that it might act through a specific receptor. Inflammation and prostaglandin synthesis is important in the development and survival of estrogendependent mammary cancers. Estrogen induced PGE2 ...

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HER-2/neu Status Is a Determinant of Mammary Aromatase Activity In vivo: Evidence for a Cyclooxygenase-2-Dependent Mechanism

Cited by 86 publications

References 46 publications

Hsp90 and PKM2 Drive the Expression of Aromatase in Li-Fraumeni Syndrome Breast Adipose Stromal Cells

Hsp90 and PKM2 Drive the Expression of Aromatase in Li-Fraumeni Syndrome Breast Adipose Stromal Cells

The Prostaglandin Transporter Regulates Adipogenesis and Aromatase Transcription

The DHEA metabolite 7β-hydroxy-epiandrosterone exerts anti-estrogenic effects on breast cancer cell lines

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