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Expression patterns of ERα66 and its novel variant isoform ERα36 in lactotroph pituitary adenomas and associations with clinicopathological characteristics

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Abstract

Purpose

The regulatory effects of estradiol on pituitary homeostasis have been well documented. However, the expression patterns of ERα66 and ERα36 and their correlations with the clinical course of postoperative prolactinoma tumors remain unclear.

Methods

The expression of ERα36, ERα66, Ki67, p53, and CD31 were determined by immunohistochemistry in 62 prolactinoma patients. Snap-frozen tumors and normal pituitaries were also examined by western blotting for estrogen receptor detection.

Results

A broad expression of ERα36 was identified in normal pituitaries. The median scores of ERα36 and ERα66 expression were 8 and 6 in normal pituitaries and 4 and 0 in tumors, respectively. Four phenotypes of ERα36 and ERα66 expression were explored in tumors with regard to sex, invasiveness, dopamine resistance, and recurrence. Low ERα36 expression was associated with tumor invasion and increased Ki67. Low ERα66 expression was associated with tumor invasion, dopamine-agonist resistance, and enhanced tumor size. Multivariable logistic regression analysis showed that low ERα36 expression is an independent risk factor for invasiveness. The significant inverse association of ERα66 with invasiveness, dopamine resistance, and tumor size remained significant after adjustment for sex as a potential confounder. After controlling for sex, the low ERα66/low ERα36 phenotype was 6.24 times more prevalent in invasive tumors than in noninvasive tumors. Although the decreasing trend of CD31 expression from surrounding nontumoral lactotroph adenomas to tumors was similar to that of the estrogen receptors, a significant correlation was not observed here.

Conclusion

The decreasing trends of ERα36 and ERα66 expression from normal pituitaries to tumors are associated with aggressive clinical behavior.

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Acknowledgements

The authors thank Dr. Hamideh Akbari and Dr. Nader Akbari Dilamghani for assistance with the collection of patient data and samples, Miss Fatemeh Abbaszadeh for her technical assistance and Dr. Yadollah Mehrabi for assistance with the statistical analysis.

Funding

This study was performed as a Ph.D. Thesis Project of Fatemeh Mahboobifard and was funded by the School of Medicine and Neuroscience Research Center (Grant No. A-A-725.1-1395) of Shahid Beheshti University of Medical Sciences, Iran.

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Authors and Affiliations

  1. Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Fatemeh Mahboobifard

  2. Department of Pathology, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Farahnaz Bidari-Zerehpoosh

  3. Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Science, Tehran, Iran

    Zahra Davoudi

  4. Department of Pathology, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran

    Mahshid Panahi

  5. Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Leila Dargahi

  6. Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

    Mohammad H. Pourgholami

  7. Department of Neurosurgery, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Gieve Sharifi

  8. Department of Epidemiology, School of Public Health and Safety, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Neda Izadi

  9. Department of Pharmacology and Neurobiology Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Velenjak, Tehran, Iran

    Masoumeh Jorjani

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  1. Fatemeh Mahboobifard
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Contributions

FM: Conception and design, literature search, performing the research, analysis and interpretation, writing the article. FB-Z: Evaluating the pathological sections and scoring the extent of staining. ZD: Collecting the follow-up information and revising the paper. MP: Evaluating the pathological sections and scoring the extent of staining. LD: Technical or logistic support, and revising the paper. MHP: Conception and design, revising the paper. GS: Collecting the patients’ samples. NI: Assistance with the statistical analysis. MJ: Supervision, conception and design, technical or logistic support, and revising the paper. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Masoumeh Jorjani.

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The authors declare that they have no conflict of interest.

Ethical approval

The study was approved by the Ethics Committee of the Shahid Beheshti University of Medical Science (IR.SBMU.PHNS.REC 1395.74).

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Informed consent was obtained from all patients.

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11102_2020_1029_MOESM1_ESM.pdf

Supplementary material 1 (PDF 687 kb). Supplementary Fig. 1 Immunohistochemical staining of ERα36 in a breast cancer core needle biopsy sample that was used as a positive control for ERα36 antibody. Strong positivity of ERα36 in the cytoplasm. a × 200 and b × 400. Supplementary Fig. 2 Immunohistochemical staining of ERα36 in normal pituitary tissue from the anterior pituitary gland prepared from the autopsy. More than 80% of cells show cytoplasmic expression of ERα36. a × 100 and b × 200. Supplementary Fig. 3 Immunohistochemical staining of ERα66 in two prolactinomas. a Eighty percent of cells show a strong nuclear positivity (score 12) × 400. b Sixty percent of cells show moderate nuclear positivity (score 6)

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Mahboobifard, F., Bidari-Zerehpoosh, F., Davoudi, Z. et al. Expression patterns of ERα66 and its novel variant isoform ERα36 in lactotroph pituitary adenomas and associations with clinicopathological characteristics. Pituitary 23, 232–245 (2020). https://doi.org/10.1007/s11102-020-01029-z

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