Estrogen receptor α/prolactin receptor bilateral crosstalk promotes bromocriptine resistance in prolactinomas

Abstract

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.

Luteal expression of factors involved in the metabolism and sensitivity to oestrogens in the dog during pregnancy and in non‐pregnant cycle

“…Last but not least, when the local, that is, intraluteal, activity of oestrogens is considered, the possible role of E2 in regulating the expression of the PRL receptor (PRLR) should be taken into account. Such a mechanism has been shown in other species and organs, for example, in the brain of rats or human pituitary adenoma (DeVito et al., 1992 ; Shamgochian et al., 1995 ; Xiao et al., 2020 ).…”

Dopamine Agonist-Resistant Microprolactinoma—Mechanisms, Predictors and Management: A Case Report and Literature Review

“…In a study on 90 patients with lactotroph adenoma, Su et al found that increased expression of oestrogen receptor β (ER-β) in prolactinoma tissue was correlated with DA-resistance [ 13 ]. Similarly, Xiao et al showed that increased levels of ERα and PRL receptor protein expression were detected in BRC-resistant prolactinoma cell lines [ 2 ]. Of note, ERα inhibition restored BRC sensitivity in pituitary adenoma cells [ 2 ].…”

“…Similarly, Xiao et al showed that increased levels of ERα and PRL receptor protein expression were detected in BRC-resistant prolactinoma cell lines [ 2 ]. Of note, ERα inhibition restored BRC sensitivity in pituitary adenoma cells [ 2 ]. A number of studies have evaluated the role of selective oestrogen receptor modulators (SERMs) in prolactinoma patients; however, the available data on the use of those agents are limited and inconclusive [ 5 ].…”

“…Prolactinomas are the most common type of functional, hormone-secreting pituitary adenomas, accounting for about 40% of total pituitary adenomas [ 1 , 2 , 3 ]. They usually occur in young females, and up to 80% of them are microadenomas (<10 mm) [ 4 ].…”

Molecular Pathways in Prolactinomas: Translational and Therapeutic Implications

“…More recently, Xiao Z et al [59] investigated the effects of αER and PRLR signalling cross-talk in the bromocriptine-resistant prolactinoma cell line. Surprisingly, they found increased levels of ERα and PRLR protein expression in bromocriptine-resistant prolactinomas.…”