Prognostic and Therapeutic Implications of Aromatase Expression in Lung Adenocarcinomas with <i>EGFR</i> Mutations

Kohno, Mikihiro; Okamoto, Tatsuro; Suda, Kenichi; Shimokawa, Mototsugu; Kitahara, Hiromoto; Shimamatsu, Shinichiro; Konishi, Hideyuki; Yoshida, Tsukihisa; Takenoyama, Mitsuhiro; Yano, Tokujiro; Maehara, Yoshihiko

doi:10.1158/1078-0432.ccr-13-2683

Cited by 35 publications

(30 citation statements)

References 43 publications

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“…A recent study underscores the emerging importance of aromatase expression in neoplastic tissues in addition to ER-positive breast carcinoma (15). This study examined CYP19A1 expression in patients with lung adenocarcinoma and suggests that aromatase expression is a prognostic factor for this disease in female subjects.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Pharmacological Evaluation of Letrozole as a Novel Treatment for Gliomas

Dave

Chow

Gudelsky

et al. 2015

Molecular Cancer Therapeutics

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We present data that letrozole, an extensively used aromatase inhibitor in the treatment of estrogen receptor-positive breast tumors in postmenopausal women, may be potentially used in the treatment of glioblastomas. First, we measured the in vitro cytotoxicity of letrozole and aromatase (CYP19A1) expression and activity in human LN229, T98G, U373MG, U251MG, and U87MG, and rat C6 glioma cell lines. Estrogen receptor (ER)positive MCF-7 and ER-negative MDA-MB-231 cells served as controls. Cytotoxicity was determined employing the MTT assay, and aromatase activity using an immunoassay that measures the conversion of testosterone to estrogen. Second, in vivo activity of letrozole was assessed in Sprague-Dawley rats orthotopically implanted with C6 gliomas. The changes in tumor volume with letrozole treatment (4 mg/kg/day) were assessed employing μPET/CT imaging, employing [18F]-fluorodeoxyglucose (F18-FDG) as the radiotracer. Brain tissues were collected for histologic evaluations. All glioma cell lines included here expressed CYP19A1 and letrozole exerted considerable cytotoxicity and decrease in aromatase activity against these cells (IC50, 0.1–3.5 μmol/L). Imaging analysis employing F18-FDG μPET/CT demonstrated a marked reduction of active tumor volume (>75%) after 8 days of letrozole treatment. Immunohistochemical analysis revealed marked reduction in aromatase expression in tumoral regions of the brain after letrozole treatment. Thus, employing multifaceted tools, we demonstrate that aromatase may be a novel target for the treatment of gliomas and that letrozole, an FDA-approved drug with an outstanding record of safety may be repurposed for the treatment of such primary brain tumors, which currently have few therapeutic options.

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Section: Discussionmentioning

confidence: 99%

Preclinical Pharmacological Evaluation of Letrozole as a Novel Treatment for Gliomas

Dave

Chow

Gudelsky

et al. 2015

Molecular Cancer Therapeutics

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“…Clinicopathological features, including age at surgery, sex, smoking history, tumor differentiation, pathological tumor-node-metastasis (TNM) stage (seventh edition of the lung cancer staging system), pleural or lymphovascular invasion, histological subtype (World Health Organization Classification 2015), surgical procedure, and epidermal growth factor receptor ( EGFR ) mutation status, were examined. EGFR status had been determined in tumor tissues using the peptide nucleic acid-locked nucleic acid (PNA-LNA) polymerase chain reaction clamp method (Mitsubishi Chemical Medience, Tokyo, Japan) in 235 specimens [25]. Briefly, systemic dissection of hilar and mediastinal lymph nodes was performed at the same time as pulmonary lobectomy.…”

Section: Methodsmentioning

confidence: 99%

Clinical implications of the novel cytokine IL-38 expressed in lung adenocarcinoma: Possible association with PD-L1 expression

et al. 2017

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Interleukin (IL)-38, a novel member of the IL-1 cytokine family, is homologous to IL-1 receptor antagonist (IL-1Ra) and IL-36Ra, and has been reported to act as an antagonist. IL-38 expression is found in tonsil, placenta, and spleen, and recent studies suggest an association between IL-38 and autoimmune diseases. However, whether IL-38 plays a role in carcinogenesis or cancer growth is unclear. In the present study, we identified increases in IL-38 expression by immunohistochemistry in multiple types of cancer cells. In the examination of 417 surgically resected primary lung adenocarcinomas, Fisher’s exact tests showed significant associations between high IL-38 expression and high tumor grades, an advanced T status, advanced N status, advanced stage, and the presence of pleural and vessel invasions. Survival analyses by the Kaplan-Meier method showed that patients with high expression of IL-38 had significantly shorter disease-free survival and shorter overall survival after surgery than patients with low expression of IL-38 (log-rank test: P = 0.0021 and P = 0.0035, respectively). Moreover, programmed cell death-ligand 1 (PD-L1)-positive cases showed higher expression of IL-38 than PD-L1-negative cases (Wilcoxon rank-sum test: P < 0.0001). In conclusion, IL-38 was expressed in tumor cells of various cancers, and IL-38 expression was associated with poor survival of lung adenocarcinoma patients. IL-38 may affect host immunity or the tumor microenvironment, and contribute to the progression of lung adenocarcinoma.

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“…Although there is only weak evidence that estrogen exposure to lung tissue induces lung cancer in clinical practice (22), several studies have demonstrated that intra-tumor aromatase expression (8,10,15,16,18,21) exhibits an association with poorer prognoses. The present study did not indicate statistically significant associations between aromatase expression and pathological invasiveness.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have focused on hormonal receptors due to patients with smoking-independent lung cancers being mainly female (3,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Estrogen exposure measured by an indirect method could only demonstrate a weak association between female hormone-associated factors and lung cancer (22).…”

Section: Introductionmentioning

confidence: 99%

“…Estrogen exposure measured by an indirect method could only demonstrate a weak association between female hormone-associated factors and lung cancer (22). Intratumoral estrogen expression has been demonstrated to increase tumor proliferation (10) and worse prognosis (8). However the association between prognosis outcomes and expression of receptors stimulated by increased intratumoral estrogen remain inconsistent (11,14,21,23).…”

Section: Introductionmentioning

confidence: 99%

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Exon 7 splicing variant of estrogen receptor α is associated with pathological invasiveness in smoking-independent lung adenocarcinoma

et al. 2017

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Abstract.Patients with smoking-independent lung cancer mainly consist of females, yet the molecular background of this epidemiological feature, other than epidermal growth factor receptor (EGFR) mutation, remains unclear. Several studies have revealed the association between female hormone-associated factors and the prognosis of lung cancer, however the data remain inconsistent. The present study focused on the expression of estrogen receptor (ER)α in order to elucidate this association in smoking-independent lung cancer. Immunohistochemistry staining (IHC) of aromatase, ERα and ERβ was performed against formalin-treated tissues from 38 patients who had never-smoked who underwent complete surgical resection between 2012 and 2013. Among them, adequate RNA of the tumor and adjacent normal lung cancer was extracted from 31 matching deep frozen samples. Considering the IHC results, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to measure the expression level of 2 different exons of ERα, exon 6 and exon 7, which are part of the ligand binding domain of ERα, using the Taqman gene expression assay. Extra-nuclear expression of ERα using IHC demonstrated a statistically significant association with pathological invasiveness. RT-qPCR results exhibited a decreased expression of ERα exon 7 in invasive tumor tissues, compared with their adjacent normal tissues. This is consistent with the findings of previous in vitro studies indicating that extra-nuclear ERα were exon 7 splicing variants. No difference was observed in ERα exon 7 expression between normal and tumor tissues in non-invasive lung cancer tissues. When considering the EGFR mutation status, EGFR wild-type lung cancers exhibited decreased ERα exon 7 expression levels compared with EGFR mutated lung cancers. Extra-nuclear expression of ERα, which may represent exon 7 splicing variants of ERα, showed statistical association with pathological invasiveness in smoking-independent lung cancer. The post-translational splicing mechanism of ERα may be involved in the acquired invasiveness of smoking independent lung cancer.

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Prognostic and Therapeutic Implications of Aromatase Expression in Lung Adenocarcinomas with EGFR Mutations

Cited by 35 publications

References 43 publications

Preclinical Pharmacological Evaluation of Letrozole as a Novel Treatment for Gliomas

Preclinical Pharmacological Evaluation of Letrozole as a Novel Treatment for Gliomas

Clinical implications of the novel cytokine IL-38 expressed in lung adenocarcinoma: Possible association with PD-L1 expression

Exon 7 splicing variant of estrogen receptor α is associated with pathological invasiveness in smoking-independent lung adenocarcinoma

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