Progesterone Receptor in Non–Small Cell Lung Cancer—A Potent Prognostic Factor and Possible Target for Endocrine Therapy

Ishibashi, Hiroyuki; Suzuki, Takashi; Suzuki, Satoshi; Niikawa, Hiromichi; Lu, Liangying; Miki, Yasuhiro; Moriya, Takuya; Hayashi, Shin Ichi; Handa, Masashi; Kondo, Takashi; Sasano, Hironobu

doi:10.1158/0008-5472.can-04-3087

Cited by 154 publications

(159 citation statements)

References 46 publications

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“…A great majority of breast carcinomas are positive for ERa and SERMs such as tamoxifen or aromatase inhibitors such as letrozole are being used clinically as antiendocrine therapies for ERa-positive breast carcinoma patients. In NSCLC, ERh immunoreactivity has been found to be frequently positive (6,14,27,28), whereas the status of ERa immunoreactivity showed marked variability in its frequency of immunopositivity (0-73%) among the different studies reported (5, 14, 27, 29 -31). In these previously reported investigations, the same ERa antibody employed in our present study (clone 6F11) was used in three groups, in which ERa positivity was 0% (30), 38% (14), and 66% (29).…”

Section: Discussionmentioning

confidence: 99%

“…In NSCLC, ERh immunoreactivity has been found to be frequently positive (6,14,27,28), whereas the status of ERa immunoreactivity showed marked variability in its frequency of immunopositivity (0-73%) among the different studies reported (5, 14, 27, 29 -31). In these previously reported investigations, the same ERa antibody employed in our present study (clone 6F11) was used in three groups, in which ERa positivity was 0% (30), 38% (14), and 66% (29). In addition, Dabbs et al (29) reported that nuclear ERa immunoreactivity was detected with the 6F11 clone but not with the 1D5 clone, and these authors suggested that variability in ERa immunoreactivity might be due to different epitope recognized by the antibodies used in the study.…”

Section: Discussionmentioning

confidence: 99%

“…Subsequently, the percentage of immunoreactivity, labeling index (LI), was determined. Cases with ERa or ERh LI of >10% were considered ERa-or ERh-positive NSCLC as reported previously (14). Immunoreactivity for 17hHSD1 was detected in the cytoplasm of carcinoma cells, and cases that had >10% of positive carcinoma cells were considered positive (15).…”

Section: Methodsmentioning

confidence: 96%

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

Niikawa

Suzuki²,

Miki

et al. 2008

Clinical Cancer Research

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175

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Purpose: The possible involvement of gender-dependent factors has been suggested in human non-small cell lung carcinomas (NSCLC), but their precise roles remain largely unclear. Therefore, we examined intratumoral estradiol concentrations in NSCLC to examine local actions of estrogens in NSCLC. Experimental Design: Fifty-nine frozen specimens of NSCLC were available for liquid chromatography/electrospray tandem mass spectrometry to study intratumoral estradiol concentrations. In addition, A549 NSCLC cells stably expressing estrogen receptor (ER) a (A549 + ERa) or ERh (A549 + ERh) were used in vitro studies. Results: Forty-three (73%) of 59 NSCLC showed higher concentration of estradiol in carcinoma tissues than the corresponding nonneoplastic lung tissues from the same patient, and intratumoral estradiol concentrations were significantly (P = 0.0002 and 2.2-fold) higher than the corresponding nonneoplastic lungs. The intratumoral concentration of estradiol was positively correlated with aromatase expression, tumor size, and Ki-67 status in ERa-or ERh-positive cases. In in vitro studies, estradiol significantly increased cell proliferation of A549 + ERa orA549 + ERh, which was significantly suppressed by selective ER modulators, tamoxifen or raloxifene. Both A549 + ERa and A549 + ERh cells expressed aromatase. The cell proliferation level in these cells was significantly increased under treatment with testosterone, and it was inhibited by addition of the aromatase inhibitor letrozole. Conclusions: These results suggest that estradiol is locally produced in NSCLC mainly by aromatase and plays an important role in the growth of ERa-or ERh-positive NSCLC. Therefore, use of selective ER modulators and/or aromatase inhibitors may be clinically effective in NSCLC that are positive for both ER and aromatase.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 96%

See 1 more Smart Citation

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

Niikawa

Suzuki²,

Miki

et al. 2008

Clinical Cancer Research

Self Cite

175

213

View full text Add to dashboard Cite

show abstract

“…In our previous studies (7,16), we showed that A549, provided by Cell Resource Center for Biomedical Research (Tohoku University, Sendai, Japan), did not have detectable levels of ERα and ERβ proteins and was unresponsive to estradiol treatment in reporter gene assay. A549 used in this study was the same stock as in the previous study (16). Estradiol and testosterone were obtained from Sigma-Aldrich.…”

Section: Lung Carcinoma Cell Lines and Culture Conditionsmentioning

confidence: 95%

Intratumoral Localization of Aromatase and Interaction between Stromal and Parenchymal Cells in the Non–Small Cell Lung Carcinoma Microenvironment

et al. 2010

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Estrogens produced as a result of intratumoral aromatization has been recently shown to play important roles in proliferation of human non-small cell lung carcinomas (NSCLC), but the details have remained largely unknown. Therefore, in this study, we evaluated the possible roles of intratumoral aromatase in NSCLCs as follows: (a) evaluation of intratumoral localization of aromatase mRNA/protein in six lung adenocarcinoma cases using laser capture microdissection combined with quantitative reverse transcriptase-PCR and immunohistochemistry; (b) examination of the possible effects of isolated stromal cells from lung carcinoma tissues on aromatase mRNA transcript expression in lung carcinoma cell lines (A549 and LK87) through a coculture system; and (c) screening of cytokines derived from stromal LK001S and LK002S cells using cytokine antibody arrays and subsequent evaluation of effects of these cytokines on aromatase expression in A549 and LK87. Both aromatase mRNA and protein were mainly detected in intratumoral carcinoma cells but not in stromal cells. Aromatase expression of A549 and LK87 was upregulated in the presence of LK001S or LK002S cells. Several cytokines such as interleukin-6 (IL-6), oncostatin M, and tumor necrosis factor-α, all known as inducible factors of aromatase gene, were detected in conditioned media of LK001S and LK002S cells. Treatment of both oncostatin M and IL-6 induced aromatase gene expression in A549 an LK87, respectively. These results all indicated that intratumoral microenvironments, especially carcinoma-stromal cell interactions, play a pivotal role in the regulation of intratumoral estrogen synthesis through aromatase expression in human lung adenocarcinomas. Cancer Res; 70(16); 6659-69. ©2010 AACR.

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“…It is believed that the physiological action of P4 is mediated through either nuclear PR or membrane-bound receptors. A549 cells were reported to be nPR positive in previous research (32). To exclude the possibility that nPR could mediate the effect of P4 in A549 cells, we applied a pre-incubation of MIF, a P4 antagonist.…”

Section: Molecular Pathways Involved In the P4+pp1-induced Cell Migramentioning

confidence: 99%

Progesterone inhibits the migration and invasion of A549 lung cancer cells through membrane progesterone receptor α-mediated mechanisms

et al. 2013

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Abstract. Lung cancer is the leading cause of cancer morbidity and mortality in the world. The incidence of lung cancer, particularly lung adenocarcinoma, is increasing in women compared to men. The role of sex hormones in the development of lung cancer has attracted substantial interest, but remains largely unknown. In this study, we demonstrated that membrane progesterone receptor α (mPRα) was expressed in a lung adenocarcinoma cell line, A549, and was located on the cell membrane. In additional experiments, we found that mPRα functioned as an essential mediator for progesterone (P4)-induced inhibitory effects on cell migration and invasion of A549 cells. Furthermore, PP1 (an Src pathway inhibitor), when co-incubated with P4, synchronously enhanced the inhibitory effects of P4 on cell migration and invasion. To explore the mechanisms of inhibition, we found that P4 and PP1 induced a cascade of molecular signaling events, such as dephosphorylation of focal adhesion kinase (FAK) and downregulation of matrix metalloproteinase 9 (MMP-9). Our study provides a mechanistic view on the effects of P4 through mPRα→Src/FAK relevant pathways in human lung adenocarcinoma cells and may aid in the development of novel therapeutic tools for the treatment of lung cancer. IntroductionLung cancer is the leading cause of morbidity and mortality in malignant tumors. Non-small cell lung cancer (NSCLC) accounts for 80% of lung cancer cases. Epidemic studies reveal gender differences in NSCLC patients, particularly in lung adenocarcinoma. Women are more susceptible to smoke or other environmental factors (1), in view of the fact that estrogen and progesterone are well-known prognostic factors for breast, endometrial and ovarian cancer, suggesting a possible involvement of gender-dependent factors in the pathogenesis and/or development of NSCLCs (2).Sex hormones and their receptors have been the focus of considerable cancer research. Among sex steroids, estrogens play an important role in the development of breast and endometrial carcinoma, whereas androgens significantly contribute to the development of prostate cancer (3). By contrast, progesterone generally promotes differentiation and inhibits cellular proliferation through the nuclear progesterone receptor (nPR) (4). Previous studies showed that progesterone-mediated growth inhibition was mainly preceded by decreased expression of cyclins and/or induction of cyclin-dependent kinase inhibitors (5-7). Administration of progestins, including medroxyprogesterone acetate, is currently used as an endocrine therapy in breast and endometrial carcinoma patients (8,9). During embryogenesis, sex hormones influence the development of lung tissue, but during adulthood, the lung is not a target organ for sex hormones. Notably, female adenocarcinoma has a better prognosis than male lung cancer or other female pathologic types of lung cancer, indicating gender as an independent prognostic factor (10). It is reported that progesterone can mediate growth inhibition in PR-positive tumors in mice th...

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Progesterone Receptor in Non–Small Cell Lung Cancer—A Potent Prognostic Factor and Possible Target for Endocrine Therapy

Cited by 154 publications

References 46 publications

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

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

Intratumoral Localization of Aromatase and Interaction between Stromal and Parenchymal Cells in the Non–Small Cell Lung Carcinoma Microenvironment

Progesterone inhibits the migration and invasion of A549 lung cancer cells through membrane progesterone receptor α-mediated mechanisms

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