Isolation and characterization of a complementary DNA specific for human aromatase-system cytochrome P-450 mRNA.

Evans, Claudia T.; Ledesma, Diana B.; Schulz, Tanya Z.; Simpson, Evan R.; Mendelson, Carole R.

doi:10.1073/pnas.83.17.6387

Cited by 74 publications

(38 citation statements)

References 35 publications

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“…Evans et al [26] reported the occurrence of three mRNAs (3.0, 2.7 and 2.4 kb) for human placental P-450ARoM. They dS0 isolated tW0 P-&&ROM cDNAs of different length and suggested that the two major mRNAs are formed by differential RNA processing [lo].…”

Section: Discussionmentioning

confidence: 99%

Alternative usage of different poly(A) addition signals for two major species of mRNA encoding human aromatase P‐450

Toda¹,

M²,

Mitsuuchi³

et al. 1989

FEBS Letters

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Two cDNA clones for human placental aromatase P-450 (P-450 AROM) have been isolated and sequenced. The insert of one clone (2894 bp) contains an open reading frame encoding a protein consisting of 503 amino acid residues together with a 49 bp S-untranslated stretch and a 1336 bp 3'-noncoding region to which a poly(A) tract is attached. Three potential poly(A) addition signals are detected in this 3'noncoding region. The other clone contains a shorter cDNA insert, the nucleotide sequence of which overlaps with most of the sequence of the longer cDNA insert (nucleotides 36-2355) except for one nucleotide substitution. The 3'noncoding region of this shorter cDNA is only 846 bp in length, but a poly(A) tract is also attached to its 3'-terminus. Northern blot analysis of human placental RNA reveals the presence of two major mRNA species of 3.4 and 2.9 kb when probes excised from the overlapping region of these two cDNAs are employed. The 2.9 kb mRNA is not detected, however, when a fragment of the non-overlapping region of the longer cDNA is used as a probe. It is therefore concluded that the two major species of P-4SOAROM mRNA are formed as a consequence of alternative processing of precursor mRNA(s).

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Section: Discussionmentioning

confidence: 99%

Alternative usage of different poly(A) addition signals for two major species of mRNA encoding human aromatase P‐450

Toda¹,

M²,

Mitsuuchi³

et al. 1989

FEBS Letters

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show abstract

“…To provide a model in which to test antitumor efficacy of aromatase inhibitors, MCF-7 cells were transfected with the human aromatase cDNA (17). MCF-7Arom5 expresses high aromatase levels (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Full-length human placental aromatase cDNA (17) was introduced into pcDNA3.0 and transfected into MCF-7. Clones were selected and screened for aromatase expression.…”

Section: Methodsmentioning

confidence: 99%

Combined Src and Aromatase Inhibition Impairs Human Breast Cancer GrowthIn vivoand Bypass Pathways Are Activated in AZD0530-Resistant Tumors

Chen

Guggisberg

Jordà

et al. 2009

Clinical Cancer Research

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Purpose: Antiestrogens are used to treat estrogen receptor (ER)-α-positive breast cancers and cause a p27-dependent G 1 arrest. Estrogen-bound ER recruits Src to mediate proteolysis of p27 and drive cell proliferation. Here, we tested the antitumor efficacy of combined Src and aromatase inhibition for ER-positive breast cancer. Experimental Design: Antiproliferative effects of the aromatase inhibitor, anastrozole, and Src inhibitor, AZD0530, alone or in combination were tested in vitro and in vivo on aromatase-transfected MCF-7Arom5 xenografts. Xenografts were analyzed by immunohistochemistry and proteomic analysis to identify potential biomarkers of drug response and resistance. Results: AZD0530 and anastrozole together increased p27 and caused greater G 1 cell cycle arrest than either drug alone. AZD0530 monotherapy initially retarded xenograft growth in vivo, but drug resistance rapidly emerged. Combined anastrozole/AZD0530 reduced drug resistance and showed greater antitumor efficacy in vivo with greater Src and epidermal growth factor receptor inhibition and a greater increase in p27 and reduction of Ki-67 than either drug alone, supporting further evaluation of these putative predictors of response to combined Src/aromatase inhibition in vivo. Anastrozole alone stimulated Src activity both in vitro and in vivo. AZD0530-resistant tumors showed activation of bypass pathways including MEK and phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin, raising the possibility that MEK, mammalian target of rapamycin (mTOR), or PI3K inhibitors may augment Src inhibitor efficacy. Conclusions: These data support clinical investigation of anastrozole-AZD0530 therapy for postmenopausal ER-positive breast cancer. Loss of p27 and increased Ki-67 may predict response and further clinical studies should evaluate for activation of bypass pathways including MEK and PI3K pathways during Src inhibitor therapy.Estrogen is a potent mitogen and a survival factor for many estrogen receptor (ER)-α-positive human breast cancer lines and appears to play a role in the genesis and progression of a majority of breast cancers. ER blockade and drug-mediated estrogen deprivation are used in ER-positive breast cancer both as adjuvant treatments to prevent recurrence after initial breast surgery and for metastatic disease (1). Aromatase inhibitors such as anastrozole and letrozole have significantly improved the efficacy of endocrine therapy (2). Adrenal androstenedione and testosterone undergo peripheral conversion to estrogen by aromatase. Aromatase inhibitors block the last biosynthetic step in estrogen production (2) and cause >90% reduction in circulating estrogens in postmenopausal women (1). Anastrozole was the first aromatase inhibitor tested in large clinical trials in both metastatic and adjuvant settings and showed superior antitumor activity compared with tamoxifen (1, 2).Oncogenic activation of the Src tyrosine kinase regulates proliferation, motility, and survival in many human cancers (3). We observed t...

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“…tant enzyme for the progression of estrogen-dependent breast cancer, because it catalyzes the final limiting step in the biosynthesis of estrogens from androgens (1)(2)(3)(4). The levels of aromatase activity and aromatase mRNA are significantly greater in breast cancer and surrounding adipose tissues than in nonneoplastic breast tissues (5)(6)(7)(8)(9)(10).…”

mentioning

confidence: 99%

Activation of Aromatase Expression by Retinoic Acid Receptor-related Orphan Receptor (ROR) α in Breast Cancer Cells

Odawara¹,

Iwasaki²,

Horiguchi³

et al. 2009

Journal of Biological Chemistry

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Estrogen is a key regulator of the proliferation and differentiation of breast cancer cells. In addition to the estrogen supply from the ovary, estrogen is produced locally from androgen by aromatase. However, the regulation of aromatase gene expression in breast cancer has not yet been fully clarified. Retinoic acid receptor-related orphan receptor (ROR) ␣ plays an important role in the differentiation of many organs by regulating the transcription of target genes. Because aromatase and ROR␣ are expressed in breast cancer, the effect of ROR␣ on aromatase gene expression was studied. ROR␣ significantly augmented the expression of aromatase mRNA, particularly those containing exon I.4, in MCF7 cells, and aromatase activities in T47D and MCF7 cells. ROR␣ also stimulated the proliferation of these cells. Transient transfection-based reporter gene assays using the promoter at exon I.4 showed that ROR␣ augmented the transcription. A series of truncated mutation studies revealed that ROR␣ activated the transcription through ؊147 to ؉14 bp of the promoter I.4. Furthermore, ROR␣ bound to the fragment containing ؊119 to ؊107 bp of the promoter in vitro, indicating that this region may contain a novel ROR response element. Chromatin immunoprecipitation assay showed that ROR␣ bound to the region containing this site of the promoter I.4 in MCF7 cells. Moreover, we examined clinical samples and found a correlation between ROR␣ and aromatase expression. These results suggest that ROR␣ directly activates the aromatase expression to accelerate the local production of estrogen, which results in the proliferation of breast cancer cells.

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Isolation and characterization of a complementary DNA specific for human aromatase-system cytochrome P-450 mRNA.

Cited by 74 publications

References 35 publications

Alternative usage of different poly(A) addition signals for two major species of mRNA encoding human aromatase P‐450

Alternative usage of different poly(A) addition signals for two major species of mRNA encoding human aromatase P‐450

Combined Src and Aromatase Inhibition Impairs Human Breast Cancer GrowthIn vivoand Bypass Pathways Are Activated in AZD0530-Resistant Tumors

Activation of Aromatase Expression by Retinoic Acid Receptor-related Orphan Receptor (ROR) α in Breast Cancer Cells

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