Intratumoral Estrogens and Estrogen Receptors in Human Non–Small Cell Lung Carcinoma

Niikawa, Hiromichi; Suzuki, Takashi; Miki, Yasuhiro; Suzuki, Satoshi; Nagasaki, Shuji; Akahira, Jun Ichi; Honma, Sato; Evans, Dean B.; Hayashi, Shin Ichi; Kondo, Takashi; Sasano, Hironobu

doi:10.1158/1078-0432.ccr-07-1950

Cited by 174 publications

(220 citation statements)

References 35 publications

(35 reference statements)

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“…Levels of PGT are reduced in a variety of tumors including lung cancer (48). Future studies are warranted to determine whether reduced levels of PGT contribute to the elevated levels of aromatase found in some tumors (49). Given the importance of changes in expression of PGT, an influx transporter, on aromatase expression, it will also be worthwhile to determine whether multidrug resistanceassociated protein 4, an efflux transporter, plays a role in regulating aromatase expression.…”

Section: A B C D E F G H Discussionmentioning

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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Section: A B C D E F G H Discussionmentioning

confidence: 99%

The Prostaglandin Transporter Regulates Adipogenesis and Aromatase Transcription

Subbaramaiah

Hudis

Dannenberg

2011

Cancer Prevention Research

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“…7 Using in vitro examinations, Niikawa, et al showed that estradiol significantly increased cell proliferation of ER-positive lung cancer cell lines. 8 From these findings, it is speculated that lung cancer in pregnant women, whose estrogen levels are extremely high, might be largely promoted by the hormone. In the present case, lung cancer grew very rapidly and advanced to N2 disease within only 7 months.…”

Section: Discussionmentioning

confidence: 99%

Unexpected Rapid Growth of Estrogen Receptor Positive Lung Cancer during Pregnancy

Hayama

Chida

Tamura

et al. 2014

ATCS

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We report a case with lung cancer during pregnancy, which has a very poor prognosis. A 34-year old female at 30 weeks of pregnancy came to us with a cough and right lower chest pain. Chest computed tomography revealed a mass in the right lower lung lobe and the diagnosis of adenocarcinoma cT2aN1M0 was made. We performed a right sleeve pneumonectomy, as the tumor had progressed to the right main bronchus near carina. Histological sections of the specimens revealed a poorly differentiated adenocarcinoma that infiltrated surrounding structures. The pathological stage of lung cancer was T4N2M0 stage IIIB. Immunohistochemistry findings for estrogen receptor � were positive in the nuclei of the adenocarcinoma. She had a rapid recurrence in spite of chemotherapy, and she died 7.5 months after operation. The positive estrogen receptor and hormonal condition during pregnancy might promote cancer and result in her poor prognosis.Keywords: lung cancer, pregnancy, estrogen receptor IntroductionThis report describes a rare case of lung cancer during pregnancy, which is usually diagnosed at an advanced stage and has a very poor prognosis. In our case, the mass grew very rapidly during pregnancy, which might be explained by the hormonal status of the tumor. Case ReportA 34-year old female came to our outpatient clinic at 30 weeks of pregnancy complaining of a cough and right lower chest pain. She had never smoked and previously underwent a left ovariectomy due to a borderline malignant ovarian tumor. A chest computed tomography (CT) scan revealed a mass in the right lower lung lobe, surrounding the lower bronchus (Fig. 1A). A previous CT scan obtained 7 months prior during a followup examination of the ovarian tumor showed no clear nodule in the lung at that time. Two days after the chest CT scan, the patient developed dyspnea and was admitted for further examination and treatment. Complete blood cell and blood chemistry examinations were performed, which revealed white blood cells at 10600 and CRP at 10.94 mg/dl, while the serum level of carbohydrate antigen 19-9 (CA 19-9) was very high at a concentration of 1620 U/mL (normal: <37). We performed a positron emission tomography (PET) scan, as we considered that the benefits of PET scanning outweighed the radiation exposure. PET imaging showed that the standardized uptake value (SUV) of the mass in the right lower lobe was high at 7.05/8.47 (early phase/late phase), while there was no mediastinal lymph node or distant metastasis detected (Fig. 2). A bronchoscopic examination revealed narrowing of the right lower bronchus. Transbronchial biopsy findings for the We report a case with lung cancer during pregnancy, which has a very poor prognosis.A 34-year old female at 30 weeks of pregnancy came to us with a cough and right lower chest pain. Chest computed tomography revealed a mass in the right lower lung lobe and the diagnosis of adenocarcinoma cT2aN1M0 was made. We performed a right sleeve pneumonectomy, as the tumor had progressed to the right main bronchus near carina. Histolo...

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“…Using this antibody, ER-α is detected in the nucleus. Nuclear ER-α has also been detected using clone 6F11 antibody, which was raised against the full-length form of the receptor molecule [7,8,15,[17][18][19][20]25] . On the other hand, the rate of ER-α detection in NSCLC using clone 1D5 is very low, from 0%-7% [5][6][7][8]10,17,19,23,25] .…”

Section: Immunohistochemical Detection Of Er In Nsclcmentioning

confidence: 99%

“…Nucleus/cytoplasm 3%/55% Niikawa et al [15] 6F11 Nucleus 54% Nose et al [16] HC-20 Cytoplasm 84% Raso et al [17] 6F11 Nucleus 36% HC-20…”

Section: D5mentioning

confidence: 99%

Estrogen receptors as the novel therapeutic biomarker in non-small cell lung cancer

Kawai

2014

WJCO

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Although a wide range of studies have addressed the relationship between estrogen receptor (ER) expression and prognosis in non-small cell lung cancer (NSCLC), that relationship remains controversial. This is in large part because there is no consensus on the rate of ER expression in NSCLC or on the intracellular distribution of ER expression. This suggests that establishing the relationship between ER expression and prognosis will require standardization of the antibodies used as well as the definition of a positive response. For example, it is supposed from previous studies that ERs in the cytoplasm and nucleus have different relationships to prognosis than ERs in the cytoplasm. Moreover, ER signaling in NSCLC is known to be affected by aromatase, progesterone receptor and epidermal growth factor receptor mutation. However, there has been little functional analysis these mutants and subtypes. This review will focus on what is known about the role of ERs in NSCLC and whether ER can be a useful prognostic marker or therapeutic target in NSCLC.© 2014 Baishideng Publishing Group Inc. All rights reserved.Key words: Estrogen receptor; Non-small cell lung cancer; Epidermal growth factor receptor; Fulvestrant; Combined therapy Core tip: Although there were many studies regarding the role of estrogen receptor (ER) in non-small cell lung cancer (NSCLC), the rate of ER expression or the intracellular distribution of ER remains controversial. This suggests that establishing the relationship between ER expression and prognosis will require standardization of the antibodies used as well as the definition of a positive response. Furthermore, there has been little functional analysis for ER variants. This review will focus on what is known about the role of ERs in NSCLC and whether ER can be a useful prognostic marker or therapeutic target in NSCLC.Kawai H. Estrogen receptors as the novel therapeutic biomarker in non-small cell lung cancer.

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Intratumoral Estrogens and Estrogen Receptors in Human Non–Small Cell Lung Carcinoma

Cited by 174 publications

References 35 publications

The Prostaglandin Transporter Regulates Adipogenesis and Aromatase Transcription

The Prostaglandin Transporter Regulates Adipogenesis and Aromatase Transcription

Unexpected Rapid Growth of Estrogen Receptor Positive Lung Cancer during Pregnancy

Estrogen receptors as the novel therapeutic biomarker in non-small cell lung cancer

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