Enhanced expression of aromatase in p53-inactivated mammary epithelial cells

Choi, Hoo Kyun; Roh, Sang Hee; Kim, Hyung Gyoun; Han, Eun Hee; Jeong, Hye Gwang; Kang, Keon Wook

doi:10.1677/erc-07-0192

Cited by 9 publications

(8 citation statements)

References 40 publications

(27 reference statements)

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“…Consistent with our in vitro results, increased Hsp90 ATPase activity, HIF-1␣, PKM2, and aromatase expression were observed in mammary tissues of p53 null compared with p53 wild-type mice. These results are consistent with previous findings demonstrating that aromatase is elevated in p53-inactivated mammary epithelial cells (17). In this previous study, the increase in aromatase was attributed to effects on a known aromatase stimulator, CREB.…”

Section: Discussionsupporting

confidence: 93%

“…However, the complex molecular mechanisms underlying the effect of p53 on aromatase expression are poorly understood. In the present study, we have not only confirmed previous results demonstrating that p53 inhibits aromatase expression (16,17) but also have identified a novel mechanism by which this occurs in LFS stromal cells. Importantly, we show that wild-type p53 suppresses Aha1 levels leading to inhibition of Hsp90 ATPase activity.…”

Section: Discussionsupporting

confidence: 90%

“…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).…”

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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: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 90%

See 1 more Smart Citation

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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“…Two mouse studies have previously examined the relationship between p53 and aromatase. Choi and colleagues (50) found that aromatase was increased in p53-inactivated mammary epithelial cells. The increased phosphorylation and nuclear accumulation of CREB was proposed as a mechanism for the increased expression of aromatase.…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin E2 Inhibits p53 in Human Breast Adipose Stromal Cells: A Novel Mechanism for the Regulation of Aromatase in Obesity and Breast Cancer

et al. 2015

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Obesity is a risk factor for postmenopausal breast cancer and the majority of these cancers are estrogen dependent. Aromatase converts androgens into estrogens and its increased expression in breast adipose stromal cells (ASC) is a major driver of estrogen receptor-positive breast cancer. In particular, obesity-associated and tumor-derived factors, such as prostaglandin E 2 (PGE 2 ), have been shown to drive the expression of aromatase by stimulating the activity of the proximal promoter II (PII). The tumor-suppressor p53 is a key regulator of cell-cycle arrest and apoptosis and is frequently mutated in breast cancer. Mutations in p53 are rare in tumor-associated ASCs. Therefore, it was hypothesized that p53 is regulated by PGE 2 and involved in the PGE 2 -mediated regulation of aromatase. Results demonstrate that PGE 2 causes a significant decrease in p53 transcript and nuclear protein expression, as well as phosphorylation at Ser15 in primary human breast ASCs. Stabilization of p53 with RITA leads to a significant decrease in the PGE 2 -stimulated aromatase mRNA expression and activity, and PII activity. Interaction of p53 with PII was demonstrated and this interaction is decreased in the presence of PGE 2 . Moreover, mutation of the identified p53 response element leads to an increase in the basal activity of the promoter. Immunofluorescence on clinical samples demonstrates that p53 is decreased in tumor-associated ASCs compared with ASCs from normal breast tissue, and that there is a positive association between perinuclear (inactive) p53 and aromatase expression in these cells. Furthermore, aromatase expression is increased in breast ASCs from Li-Fraumeni patients (germline TP53 mutations) compared with non-Li-Fraumeni breast tissue. Overall, our results demonstrate that p53 is a negative regulator of aromatase in the breast and its inhibition by PGE 2 provides a novel mechanism for aromatase regulation in obesity and breast cancer. Cancer Res; 75(4); 645-55.Ó2015 AACR.

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“…Tamoxifen binds to the estrogen receptors (ERs) and suppresses estrogen-dependent breast cancer growth (Iwase et al, 2003). However, serious side effects can occur, including endometrial cancer, thrombosis, and embolism (Choi et al, 2008). Tamoxifen resistance can also be a problem.…”

Section: Introductionmentioning

confidence: 99%

The Inhibitory Effects of the Standardized Extracts of Ginkgo biloba on Aromatase Activity in JEG‐3 Human Choriocarcinoma Cells

Kim

Park

Chung

et al. 2013

Phytotherapy Research

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Breast cancer is the most common cancer in women worldwide. There are many endocrine adjuvant therapies for breast cancer patients that are categorized according to their mechanisms. Among them, aromatase inhibitors (AIs) that block the synthesis of estrogens have proven superiority compared with tamoxifen and have replaced it as a first-line hormonal therapy. However, AIs also have limitations due to their side effects - increased rate of bone loss and musculoskeletal complaints. We therefore need new candidate AIs with fewer side effects. The extracts of Ginkgo biloba (EGb), which contain phytochemicals from the tree, had biphasic effects for estrogens and osteoporosis-inhibiting activities in our previous experiments. In this study, we explored the possibility of EGb as an AI and their mechanisms. Aromatase activities were inhibited by EGb both in JEG-3 cells and in recombinant CYP19 microsomes. The results of polymerase chain reaction for aromatase from a coding sequence and specific promoter sequences (exon I.a, exon I.c) in JEG-3 cells as well as the results of reporter gene assays showed that EGb dose-dependently decreased the aromatase gene expression. The decreased protein levels were demonstrated by Western blotting. From these results, we concluded that EGb could act as an AI at both the enzyme and transcriptional levels.

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Enhanced expression of aromatase in p53-inactivated mammary epithelial cells

Cited by 9 publications

References 40 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

Prostaglandin E2 Inhibits p53 in Human Breast Adipose Stromal Cells: A Novel Mechanism for the Regulation of Aromatase in Obesity and Breast Cancer

The Inhibitory Effects of the Standardized Extracts of Ginkgo biloba on Aromatase Activity in JEG‐3 Human Choriocarcinoma Cells

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