FKBPL Regulates Estrogen Receptor Signaling and Determines Response to Endocrine Therapy

Abstract

The HSP90 chaperone and immunophilin FKBPL is an estrogen-responsive gene that interacts with estogen receptor α (ERα) and regulates its levels. In this study, we explored the effects of FKBPL on breast cancer proliferation. Breast cancer cells stably overexpressing FKBPL became dependent on estrogen for their growth and were dramatically more sensitive to the antiestrogens tamoxifen and fulvestrant, whereas FKBPL knockdown reverses this phenotype. FKBPL knockdown also decreased the levels of the cell cycle inhibitor p21WAF1 and increased ERα phosphorylation on Ser 118 in response to 17β-estradiol and tamoxifen. In support of the likelihood that these effects explained FKBPL-mediated cell growth inhibition and sensitivity to endocrine therapies, FKBPL expression was correlated with increased overall survival and distant metastasis-free survival in breast cancer patients. Our findings suggest that FKBPL may have prognostic value based on its impact on tumor proliferative capacity and sensitivity to endocrine therapies, which improve outcome.

Targeting Treatment-Resistant Breast Cancer Stem Cells with FKBPL and Its Peptide Derivative, AD-01, via the CD44 Pathway

“…Methods were described previously (2). AD-01 treatment was added from day 2 for the duration of the experiment.…”

“…It is now well established that cancer stem cells (CSC) are considered one of the main causes of tumor recurrence and resistance to both chemoand radiotherapy (1). In breast cancer, about 40% of patients experience tumor recurrence often as distant metastasis, with only a small percentage of tumors reoccurring locally (2).…”

“…FKBPL was identified as having a role in the response of cells to radiation (21,22). In a complex with Hsp90, FKBPL stabilizes p21 (23) and regulates estrogen receptor (ER), androgen receptor, and glucocorticoid receptor signaling (2,24,25). Furthermore, in breast cancer, because of FKBPL's association with ER, FKBPL has shown potential as both a prognostic and predictive biomarker of response to endocrine therapy (2,26).…”

“…In a complex with Hsp90, FKBPL stabilizes p21 (23) and regulates estrogen receptor (ER), androgen receptor, and glucocorticoid receptor signaling (2,24,25). Furthermore, in breast cancer, because of FKBPL's association with ER, FKBPL has shown potential as both a prognostic and predictive biomarker of response to endocrine therapy (2,26). However, the most recently identified role for FKBPL is as a secreted antiangiogenic protein, which is dependent on CD44 for its activity (27,28), and more recently, we have generated data that strongly suggests that FKBPL/AD-01 bind and regulate CD44 (28).…”

Daidzein–Estrogen Interaction in the Rat Uterus and Its Effect on Human Breast Cancer Cell Growth

“…For instance, subtle differences in ER conformations caused by (1) interaction with different ligands interacting with different co-activators or co-repressors within the cell; 50 (2) the existence of spliced receptor variants such as ER36 51,52 or ER46; 53 (3) recruitment of co-regulators by the orphan nuclear ERRa in a ligand-independent manner, 54-56 thus decreasing their availability for interaction with remaining ERs in some cell types but not others; (4) presence of different molecular chaperones such as FKBP51, FKBP52, and Cyp40, which may be incorporated in the inactivated ER complexes from the different cell types; 57,58 or simply, (5) that some of the responses are not ER-mediated responses. In the case of differences between human breast cancer cell lines MCF-7 and MDA-MB-231, differences had been explained by the role of the ERa46 isoform in cellular proliferation.…”