Subcellular Localization of Cyclic AMP-Responsive Element Binding Protein-Regulated Transcription Coactivator 2 Provides a Link between Obesity and Breast Cancer in Postmenopausal Women

Brown, Kristy A.; McInnes, Kerry J.; Hunger, Nicole I.; Oakhill, Jonathan S.; Steinberg, Gregory R.; Simpson, Evan R.

doi:10.1158/0008-5472.can-09-0108

Cited by 106 publications

(122 citation statements)

References 51 publications

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“…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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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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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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“…2). 26 Consistent with this, we have shown that the CRTC2 mutant S171A remains in the nucleus and stimulates aromatase PII activity, whereas the S171D mutant remains in the cytoplasm and cannot stimulate PII activity. (S171 is the site of phosphorylation by AMPK.)…”

supporting

confidence: 80%

Estrogens, Obesity, Inflammation, and Breast Cancer—What Is the Link?

Brown

Simpson

2015

Semin Reprod Med

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Our work on breast cancer concerns the role of local aromatase expression in the breast as the source of estrogen driving breast cancer development in the postmenopausal woman. 1,2 Following the menopausal transition, the ovaries cease to make estrogens, which then becomes the responsibility of extragonadal sites such as breast, bone, and brain. Work from our laboratory and others indicates that estrogen produced in these sites acts locally rather than systemically in a paracrine and intracrine fashion. 3,4 Thus, in the case of the breast, our goal has been to define the mechanisms whereby aromatase expression is regulated within the breast, with the translational goal of developing new breast-specific inhibitors of aromatase expression as improved endocrine therapy for breast cancer treatment and prevention. Aromatase in the Breast, Aging, and Breast CancerWithin the breast, aromatase expression occurs in the adipose mesenchymal cells and increases fourfold in the presence of a tumor. 3 This occurs in conjunction with differential promoter usage such that the gonadal proximal promoter PII dominates relative to the promoter I.4. [5][6][7] We and others have shown that this is because inflammatory factors such as prostaglandin E 2 produced by the tumorous epithelium Keywords ► estrogens ► obesity ► inflammation ► breast cancer AbstractIt gives me great pleasure to contribute to this special issue of Seminars which honors the career of Bruce Carr. As it happens, Bruce was my first Fellow upon my arrival at the Green Center for Reproductive Biology Sciences at UT Southwestern Medical Center in 1977. At that time, the Center was filled with luminaries of Reproductive Endocrinology, such as John Porter, Jack Johnston, Norman Gant, and of course the Director, Paul MacDonald, so to be given the responsibility of mentoring a new Fellow was a daunting responsibility. However, Bruce quickly rolled up his sleeves and plunged straight in, and we forged a relationship which led to some 36 manuscripts in 4 years. The first of these was entitled "The Role of Serum Lipoproteins in Steroidogenesis by the Human Fetal Adrenal Cortex," published in the Journal of Clinical Endocrinology and Metabolism, volume 49, pages 146-148, in 1979, and the authors were Simpson ER, Carr BR, Parker CR Jr, Milewich L, Porter JC, and MacDonald PC. Bruce quickly moved up the ranks of the Obstetrics/Gynecology Department to become full Professor and we went our separate ways professionally, but we remain close friends to this day. This special issue is indeed a worthy tribute to an outstanding career and especially to Bruce's role as editor-in-chief of Seminars which he has guided through the rapid evolution of the specialty, always maintaining a strong research focus and thus carrying on the rich tradition of the Green Center and the Obstetrics/Gynecology Department.

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“…Elevated circulating estrogen levels, as a result of increased peripheral aromatization of androgens, have been indicated to underlie the association between obesity and a higher risk of breast cancer in postmenopausal women (Brown et al 2009, Brown & Simpson 2010). In the present study, we showed that both PI.4-and PII-driven aromatase transcription can be efficiently suppressed by MSA, leading to a marked downregulation of aromatase mRNA, protein, and thereby activity.…”

Section: Discussionsupporting

confidence: 57%

“…A number of transcription factors have been implicated in PII regulation, including LRH-1, CREB, CRTC2, ATF2, SF-1, C/EBPs, Jun, and several orphan nuclear receptors , Clyne et al 2002, Yang et al 2002, Sofi et al 2003, Ghosh et al 2008, Kijima et al 2008, Brown et al 2009). PI.4 is a TATA-less promoter that contains a glucocorticoid response element, Sp1-binding site, and an interferon-g activation site element (Zhao et al 1996b).…”

Section: Discussionmentioning

confidence: 99%

“…elevated leptin level, can activate strong PII-induced aromatase expression in the peripheral adipose tissue of obese women, resulting in elevated peripheral aromatization of androgens and increased circulating estrogen levels (Geisler et al 2007, Maccio et al 2009, Hursting 2011. This may underlie the association between obesity and increased risk of breast cancer in postmenopausal women (Brown et al 2009, Brown & Simpson 2010.…”

Section: Introductionmentioning

confidence: 99%

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Methylseleninic acid is a novel suppressor of aromatase expression

Gao

Zhao²,

Liu³

et al. 2011

Journal of Endocrinology

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Elevated circulating estrogen levels, as a result of increased peripheral aromatization of androgens by aromatase, have been indicated to underlie the association between obesity and a higher risk of breast cancer in postmenopausal women. Although aromatase inhibitors have been used as a first-line therapy for estrogen receptor-positive breast cancer in postmenopausal women, their potential as breast cancer chemopreventive agents has been limited due to toxicities and high costs. It is therefore imperative to develop new aromatase-inhibiting/suppressing agents with lower toxicities and lower costs for breast cancer chemoprevention, especially in obese postmenopausal women. The expression of the aromatase gene, CYP19, is controlled in a tissuespecific manner by the alternate use of different promoters. In obese postmenopausal women, increased peripheral aromatase is primarily attributed to the activity of the glucocorticoid-stimulated promoter, PI.4, and the cAMPstimulated promoter, PII. In the present study, we show that methylseleninic acid (MSA), a second-generation selenium compound, can effectively suppress aromatase activation by dexamethasone, a synthetic glucocorticoid, and forskolin, a specific activator of adenylate cyclase. Unlike the action of aromatase inhibitors, MSA suppression of aromatase activation is not mediated via direct inhibition of aromatase enzymatic activity. Rather, it is attributable to a marked downregulation of promoters PI.4-and PII-specific aromatase mRNA expression, and thereby a reduction of aromatase protein. Considering the low-cost and low-toxicity nature of MSA, our findings provide a strong rationale for the further development of MSA as a breast cancer chemopreventive agent for obese postmenopausal women.

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Subcellular Localization of Cyclic AMP-Responsive Element Binding Protein-Regulated Transcription Coactivator 2 Provides a Link between Obesity and Breast Cancer in Postmenopausal Women

Cited by 106 publications

References 51 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

Estrogens, Obesity, Inflammation, and Breast Cancer—What Is the Link?

Methylseleninic acid is a novel suppressor of aromatase expression

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