Purpose Leydig-cell tumours (LCT) of the testis are poorly understood clinically. The aim of this report is to analyse the clinical characteristics of LCT in a large patient sample and to compare these findings with corresponding data of germ-cell tumours (GCT). Methods In a sample of 208 patients treated during 1995-2017 in 33 institutions, the following characteristics were registered: age, presenting symptoms, primary tumour size, testis-sparing surgery (TSS) or orchiectomy, malignancy, laterality, medical history, and outcome. Data analysis included descriptive statistical methods and logistic regression analysis. Results The ratio LCT:GCT is 1:23 (4.4%). The findings are as follows: median age 41 years, undescended testis 8%, bilateral LCTs 3%, malignant LCT 2.5%, contralateral GCT 2.5%, incidental detection 28%, scrotal symptoms 43%, infertility 18%, elevated estradiol levels 29%. TSS was performed in 56% with no local relapse. Of the patients with malignant LCT, one was cured through surgery. Conclusion LCT is rare, with a relative frequency (relative to GCT) of 1:23. Malignancy is found in 2.5%. LCT and GCT share a number of clinical features, e.g. bilaterality, history of undescended testis, and presenting age. TSS is safe in benign LCT. Surgery is the treatment of choice in malignant LCT.

HER2 transactivation by the HER3 ligand heregulin (HRG) promotes an endocrine-resistant phenotype in the estrogen receptor-positive (ER+) luminal-B subtype of breast cancer. The underlying biological mechanisms that link them are, however, incompletely understood. Here, we evaluated the putative role of the lipogenic enzyme fatty acid synthase (FASN) as a major cause of HRG-driven endocrine resistance in ER+/HER2-negative breast cancer cells. MCF-7 cells engineered to stably overexpress HRG (MCF-7/HRG), an in vitro model of tamoxifen/fulvestrant-resistant luminal B-like breast cancer, showed a pronounced up-regulation of FASN gene/FASN protein expression. Autocrine HRG up-regulated FASN expression via HER2 transactivation and downstream activation of PI-3K/AKT and MAPK-ERK1/2 signaling pathways. The HRG-driven FASN-overexpressing phenotype was fully prevented in MCF-7 cells expressing a structural deletion mutant of HRG that is sequestered in a cellular compartment and lacks the ability to promote endocrine-resistance in an autocrine manner. Pharmacological inhibition of FASN activity blocked the estradiol-independent and tamoxifen/fulvestrant-refractory ability of MCF-7/HRG cells to anchorage-independently grow in soft-agar. In vivo treatment with a FASN inhibitor restored the anti-tumor activity of tamoxifen and fulvestrant against fast-growing, hormone-resistant MCF-7/HRG xenograft tumors in mice. Overall, these findings implicate FASN as a key enabler for endocrine resistance in HRG+/HER2- breast cancer and highlight the therapeutic potential of FASN inhibitors for the treatment of endocrine therapy-resistant luminal-B breast cancer.