Transcriptional regulation of aromatase expression in human breast tissue

Chen, Shiuan; Itoh, Toru; Wu, Kaijin; Zhou, Dujin; Yang, Chun

doi:10.1016/s0960-0760(02)00276-5

Cited by 55 publications

(42 citation statements)

References 22 publications

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“…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)(3)(4). In normal breast adipose tissue, aromatase is expressed at low levels under the control of promoter I.…”

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confidence: 99%

“…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)(4)(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).…”

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“…Several cytokines and tumor promoters, including prostaglandin E 2 , tumor necrosis factor-␣, and interleukin-1␤ stimulate aromatase expression (4,12). 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).…”

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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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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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“…In post-menopausal women, the concentration of estrogens in breast tumor tissue is several-fold greater than those measured in plasma (5). This is related to the fact that the expression of aromatase (CYP 19), the cytochrome P 450 responsible for estrogen synthesis, is increased in breast tumors (6).…”

Section: Introductionmentioning

confidence: 98%

Ethanol stimulates the secretion of matrix metalloproteinases 2 and 9 in MCF-7 human breast cancer cells

Etique¹,

Grillier-Vuissoz²,

Flament³

2006

Oncol Rep

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Abstract. Alcohol consumption is a well-established risk factor for hormone-dependent breast cancer. In vitro studies performed to understand the mechanisms by which ethanol acts on breast cancer cells have shown that this compound stimulates both proliferation and migration. In the present study, we show by gelatin zymography that, when exposed to ethanol, MCF-7 human breast cancer cells display a higher amount of active metalloproteinases (MMP) 2 and 9 in their culture medium. This increase is somewhat higher than those observed in the case of 17ß-estradiol (E 2 ) exposure. As expected, anti-estrogen ICI 182,780 inhibits the E 2 -induced overexpression of a well-known estrogen responsive gene, the progesterone receptor, in MCF-7 cells. ICI 182,780 also inhibits the E 2 -induced increase in MMP-2 and -9 secretion. Nevertheless, in the case of ethanol exposure, this ER antagonist was only efficient on MMP-9 secretion. In addition, although MMP-9 transcription was not sensitive to E 2 or ethanol, MMP-2 transcription was stimulated in MCF-7 cells exposed to ethanol. Collectively, these results give new insights into the effects of alcohol on breast cancer cell migration, which are not due solely to an estrogen-like activity of alcohol.

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“…Aromatase participates in human sexual development and reproduction by influencing estrogen bioavailability and androgen maintenance. High aromatase expression levels have been reported in pathological conditions, such as endometriosis [2] and breast cancer [3], whereas local aromatase activity has been associated with fibroids, adenomyosis and leiomyomas [4].…”

Section: Introductionmentioning

confidence: 99%

Aromatase (CYP19) gene variants influence ovarian response to standard gonadotrophin stimulation

Lazaros

Hatzi

Xita

et al. 2011

J Assist Reprod Genet

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Purpose The association of cytochrome P450 aromatase gene CYP19(TTTA) n polymorphism with ovarian response to FSH stimulation was explored. Methods Three hundred women undergoing medically assisted reproduction and 300 women with at least one spontaneous pregnancy participated in the study. CYP19(TTTA) n polymorphism was genotyped, while serum hormones were determined. During oocyte retrieval, the follicular size, the follicle and oocyte numbers were recorded. Results Six CYP19(TTTA) n alleles with 7 to 12 repeats were revealed. Women homozygous for long CYP19(TTTA) n alleles presented with lower serum FSH levels at the third day of the menstrual cycle (p<0.001) and higher large follicle numbers (p<0.01), compared to women homozygous for short CYP19(TTTA) n alleles. The CYP19(TTTA) 7 allele was associated with higher serum FSH levels (p< 0.003), with lower total follicle (p<0.02) and large follicle numbers (p<0.03), while CYP19(TTTA) 7 allele-carriers presented more frequently with small follicles than CYP19 (TTTA) 7 allele-non carriers (p<0.01). Conclusions CYP19 genetic variants were associated with ovarian reserve and response to standard gonadotrophin stimulation of women undergoing in vitro fertilization.

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Transcriptional regulation of aromatase expression in human breast tissue

Cited by 55 publications

References 22 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

Ethanol stimulates the secretion of matrix metalloproteinases 2 and 9 in MCF-7 human breast cancer cells

Aromatase (CYP19) gene variants influence ovarian response to standard gonadotrophin stimulation

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