Dataset Information

Smoking, Sex, and Non-Small Cell Lung Cancer: Steroid Hormone Receptors in Tumor Tissue (S0424).

ABSTRACT: Background:To what extent steroid hormones contribute to lung cancer in male and female never smokers and smokers is unclear. We examined expression of hormone receptors in lung tumors by sex and smoking. Methods:Patients with primary non-small cell lung cancer were recruited into an Intergroup study in the United States and Canada, led by SWOG (S0424). Tumors from 813 cases (450 women and 363 men) were assayed using immunohistochemistry for estrogen receptor (ER)-?, ER-?, progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Linear regression was used to examine differences in expression by sex and smoking status. Cox proportional hazard models were used to estimate survival associated with the receptors. All statistical tests were two-sided. Results:In ever smokers, postmenopause and oral contraceptive use were associated with lower nuclear ER-? (P = .02) and total (nuclear + cytoplasmic) PR expression (P = .02), respectively. Women had lower cytoplasmic ER-? (regression coefficient [?], or differences in H-scores = -15.8, P = .003) and nuclear ER-? (? = -12.8, P = .04) expression than men, adjusting for age, race, and smoking. Ever smokers had both higher cytoplasmic ER-? (??=?45.0, P < .001) and ER-? (??=?25.9, P < .001) but lower total PR (? = -42.1, P < .001) than never smokers. Higher cytoplasmic ER-? and ER-? were associated with worse survival (hazard ratio = 1.73, 95% confidence interval [CI] = 1.15 to 2.58, and HR?=?1.59, 95% CI?=?1.08 to 2.33, respectively; quartiles 4 vs 1). Conclusions:Lower expression of nuclear ER-? in women supports the estrogen hypothesis in lung cancer etiology. Increasing cytoplasmic ER-? and ER-? and decreasing PR protein expression may be mechanisms whereby smoking disrupts hormone pathways.

SUBMITTER: Cheng TD

PROVIDER: S-EPMC6037104 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Smoking, Sex, and Non-Small Cell Lung Cancer: Steroid Hormone Receptors in Tumor Tissue (S0424).

Cheng Ting-Yuan David TD Darke Amy K AK Redman Mary W MW Zirpoli Gary R GR Davis Warren W Payne Ondracek Rochelle R Bshara Wiam W Omilian Angela R AR Kratzke Robert R Reid Mary E ME Molina Julian R JR Kolesar Jill M JM Chen Yuhchyau Y MacRae Robert M RM Moon James J Mack Philip P Gandara David R DR Kelly Karen K Santella Regina M RM Albain Kathy S KS Ambrosone Christine B CB

Journal of the National Cancer Institute 20180701 7

<h4>Background</h4>To what extent steroid hormones contribute to lung cancer in male and female never smokers and smokers is unclear. We examined expression of hormone receptors in lung tumors by sex and smoking.<h4>Methods</h4>Patients with primary non-small cell lung cancer were recruited into an Intergroup study in the United States and Canada, led by SWOG (S0424). Tumors from 813 cases (450 women and 363 men) were assayed using immunohistochemistry for estrogen receptor (ER)-α, ER-β, progest ...[more]

PMID: 29346580

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Project description:Estrogen receptor-? (ER?) and progesterone receptor (PR) are expressed in most human breast cancers and are important predictive factors for directing therapy. Because of de novo and acquired resistance to endocrine therapy, there remains a need to identify which ER?-positive (ER?(+))/PR-positive (PR(+)) tumors are most likely to respond. The purpose of this study was to use estrogen- and progestin-based radiopharmaceuticals to image ER? and PR in mouse mammary tumors at baseline and after hormonal therapy and to determine whether changes in these imaging biomarkers can serve as an early predictive indicator of therapeutic response.Mammary adenocarcinomas that spontaneously develop in aged female mice deficient in signal transducer and activator of transcription-1 (STAT1) were used. Imaging of ER? and PR in primary tumor-bearing mice and mice implanted with mammary cell lines (SSM1, SSM2, and SSM3) derived from primary STAT1-deficient (STAT1(-/-)) tumors was performed. Hormonal treatments consisted of estradiol, an ER agonist; letrozole, an aromatase inhibitor; and fulvestrant, a pure ER antagonist. Small-animal PET/CT was performed using (18)F-fluoroestradiol ((18)F-FES) for ER, (18)F-fluoro furanyl norprogesterone ((18)F-FFNP) for PR, and (18)F-FDG for glucose uptake. Tracer uptake in the tumor was quantified and compared with receptor concentration determined by in vitro assays of resected tumors.Primary STAT1(-/-) mammary tumors and implanted SSM2 and SSM3 tumors showed high (18)F-FES and (18)F-FFNP uptake and were confirmed to be ER?(+)/PR(+). Classic estrogen-induced regulation of the progesterone receptor gene was demonstrated by increased (18)F-FFNP uptake of estradiol-treated SSM3 tumors. Treatment with fulvestrant decreased (18)F-FFNP, (18)F-FES, and (18)F-FDG uptake and inhibited growth of SSM3 tumors but decreased only (18)F-FES uptake in SSM2 tumors, with no effect on growth, despite both tumors being ER?(+)/PR(+). Decreased (18)F-FFNP uptake by SSM3 tumors occurred early after initiation of treatment, before measurable tumor growth inhibition.Using small-animal PET, a profile was identified that distinguished fulvestrant-sensitive from fulvestrant-resistant ER?(+)/PR(+) tumors before changes in tumor size. This work demonstrates that imaging baseline tumoral (18)F-FES uptake and initial changes in (18)F-FFNP uptake in a noninvasive manner is a potentially useful strategy to identify responders and nonresponders to endocrine therapy at an early stage.

Project description:BackgroundNeoplasms of the mammary gland are among the most common diseases in female domestic dogs (Canis familiaris). It is assumed that reproductive hormones influence tumorigenesis in this species, although the precise role of the endocrine milieu and reproductive state is subject to continuing discussion. In line with this, a recent systematic review of available data on the development of mammary neoplasms revealed weak evidence for risk reduction after neutering and an effect of age at neutering. Investigation of several hormone receptors has revealed decreased expression of estrogen receptor-alpha (ERα, ESR1), progesterone (P4) receptor (PGR), prolactin (PRL) receptor (PRLR) and growth hormone receptor (GHR) associated with neoplastic differentiation of mammary tissues. In other studies, increased levels of estrogens, progesterone and prolactin were found in serum and/or tissue homogenates of dogs with malignant neoplasms. However, the association between these entities within one animal population was never previously examined. Therefore, this study investigated the association between circulating serum concentrations of estradiol-17β, progesterone and prolactin, and gene expression of ERα (ESR1), ERβ (ESR2), PGR, PRLR, PRL and GHR, with respect to reproductive state (spayed vs. intact) and cycle stage (anestrus vs. diestrus). Additionally, the expression of E-cadherin (CDH-1) was evaluated as a possible indicator of metastatic potential.ResultsFor all receptors, the lowest gene expression was found in malignant tumors compared to normal tissues of affected dogs. Steroid levels were not influenced by their corresponding receptor expression in mammary neoplasms, but increased PRL levels were negatively associated with low PRLR gene expression in malignant tumors. The expression of CDH-1 was influenced by tumor malignancy and cycle stage, i.e., the highest gene expression was found in benign mammary tumors in diestrous dogs compared to normal and malignant mammary tissues of anestrous and spayed dogs.ConclusionsHerein, it has been confirmed that transformation towards malignant neoplasms is associated with significant reduction of gene expression of particular hormone receptors. Only PRLR in malignant tumors seems to be influenced by circulating PRL levels. In dogs, CDH-1 can be used as a prognostic factor; its expression, however, in benign tumors is influenced by cycle stage.

Dataset Information

Smoking, Sex, and Non-Small Cell Lung Cancer: Steroid Hormone Receptors in Tumor Tissue (S0424).

Publications

Smoking, Sex, and Non-Small Cell Lung Cancer: Steroid Hormone Receptors in Tumor Tissue (S0424).

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