# Heterozygous Men1(+/T) Knockout Mice Do Not Develop Bronchopulmonary Neuroendocrine Hyperplasia or Neoplasia but Bronchial Adenocarcinoma

## TL;DR

Mice with a Men1 gene mutation do not develop expected lung tumors but instead develop a different type of lung cancer not seen in humans with MEN1 syndrome.

## Contribution

This study reveals that Men1 knockout mice develop bronchial adenocarcinoma instead of neuroendocrine tumors, challenging the model's accuracy for human MEN1 syndrome.

## Key findings

- Heterozygous Men1(+/T) knockout mice do not develop bronchopulmonary neuroendocrine hyperplasia or neoplasia.
- Ten percent of Men1(+/T) knockout mice develop bronchial adenocarcinoma, a condition not previously linked to human MEN1 syndrome.
- Somatostatin analog treatment did not prevent the development of bronchial adenocarcinoma in Men1(+/T) knockout mice.

## Abstract

Patients with the multiple endocrine neoplasia type 1 (MEN1) syndrome are at risk of developing tumors of the endocrine pancreas, hyperparathyroidism, and pituitary adenomas, among tumors of other organs and non-tumorous manifestations. In humans, bronchopulmonary neuroendocrine neoplasias are a rare manifestation of the MEN1 syndrome with a penetrance of 2–7%. Due to the rarity of the syndrome, this study aimed to describe pulmonary changes and identify precursor lesions of bronchopulmonary neuroendocrine neoplasias and the potential prophylactic effect of somatostatin analogues in a well-established heterozygous Men1 knockout mouse model. None of the mice in this study, somatostatin analogue-treated, or placebo-treated, developed neuroendocrine neoplasias nor precursor lesions. However, 10% of the individuals developed bronchial adenocarcinoma, which has not been described to be part of the human MEN1 syndrome to date and needs to be evaluated in future investigations.

What are the main findings?

Heterozygous Men1(+/T) knockout mice do not develop bronchopulmonary neuroendocrine hyperplasia or neoplasia.

Ten percent of Men1(+/T) knockout mice develop bronchial adenocarcinoma, a condition not previously linked to human MEN1-syndrome.

What is the implication of the main finding?

The first main finding elucidates a weakness of this animal model, which has been described as well comparable to the human MEN1 syndrome in earlier studies.

The occurrence of bronchial adenocarcinoma in these mice warrants further investigation into its potential association with human MEN1 syndrome.

Introduction: Bronchopulmonary Neuroendocrine Neoplasms (NEN) occur in 2–7% of patients with multiple endocrine neoplasia type 1 (MEN1). Precursor lesions have been identified for MEN1-related pancreatic, duodenal, and gastric NEN. The aim of the current study using a MEN1 mouse model was to define the precursor lesions of bronchopulmonary NEN and evaluate the potential prophylactic antitumor effects of somatostatin analogues in a transgenic MEN1 mouse model. Methods: Fifteen mice, germline heterozygous for Men1(+/T), were treated with subcutaneous injections of lanreotide autogel (Somatuline Autogel®, IPSEN Pharma), while 15 mice were treated with subcutaneous injections of physiologic sodium chloride as the control group. Five mice from each group were euthanized after 12, 15, and 18 months, respectively. The complete lungs were resected and evaluated after hematoxylin and eosin staining and immunohistochemistry for synaptophysin and chromogranin A. Results: In the lungs of the 30 evaluated mice, whether treated or placebo treated, no bronchopulmonary neuroendocrine cell hyperplasia nor neuroendocrine neoplasia was detected through histopathology. However, pulmonary adenocarcinoma developed in 2 (13%) of the 15 untreated mice and in 1 (7%) of the 15 lanreotide-treated mice. Conclusions: Heterozygous Men1(+/T) knockout mice do not develop bronchopulmonary NEN or precursor lesions, but pulmonary adenocarcinoma. This surprising result needs to be investigated in more detail.