1. Department of Henan Key Laboratory of Cancer Epigenetics; Cancer Institute, Department of Neurosurgery, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan 471003.
2. Department of General Practice, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan 471003.
3. Spine Tumor Center, Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai 210011.
4. Carson International Cancer Centre, Shenzhen University General Hospital and Shenzhen University Clinical Medical Academy Centre, Shenzhen University, Shenzhen, Guangdong 518000.
5. Department of Neurosurgery, Zhongnan hospital of Wuhan university, Wuhan, Hubei 430071, P.R. China.
Prolactinomas are the most common type of functional pituitary adenoma. Although bromocriptine is the preferred first line treatment for prolactinoma, resistance frequently occurs, posing a prominent clinical challenge. Both the prolactin receptor (PRLR) and estrogen receptor α (ERα) serve critical roles in the development and progression of prolactinomas, and whether this interaction between PRLR and ERα contributes to bromocriptine resistance remains to be clarified. In the present study, increased levels of ERα and PRLR protein expression were detected in bromocriptine-resistant prolactinomas and MMQ cells. Prolactin (PRL) and estradiol (E2) were found to exert synergistic effects on prolactinoma cell proliferation. Furthermore, PRL induced the phosphorylation of ERα via the JAK2-PI3K/Akt-MEK/ERK pathway, while estrogen promoted PRLR upregulation via pERα. ERα inhibition abolished E2-induced PRLR upregulation and PRL-induced ERα phosphorylation, and fulvestrant, an ERα inhibitor, restored pituitary adenoma cell sensitivity to bromocriptine by activating JNK-MEK/ERK-p38 MAPK signaling and cyclin D1 downregulation. Collectively, these data suggest that the interaction between the estrogen/ERα and PRL/PRLR pathways may contribute to bromocriptine resistance, and therefore, that combination treatment with fulvestrant and bromocriptine (as opposed to either drug alone) may exert potent antitumor effects on bromocriptine-resistant prolactinomas.
Keywords: estrogen receptor α, prolactin receptor, bromocriptine, prolactinoma