FKBPL: a marker of good prognosis in breast cancer

Abstract

FK506-binding protein-like (FKBPL) has established roles as an anti-tumor protein, with a therapeutic peptide based on this protein, ALM201, shortly entering phase I/II clinical trials. Here, we evaluated FKBPL's prognostic ability in primary breast cancer tissue, represented on tissue microarrays (TMA) from 3277 women recruited into five independent retrospective studies, using immunohistochemistry (IHC). In a meta-analysis, FKBPL levels were a significant predictor of BCSS; low FKBPL levels indicated poorer breast cancer specific survival (BCSS) (hazard ratio (HR) = 1.30, 95% confidence interval (CI) 1.14–1.49, p < 0.001). The prognostic impact of FKBPL remained significant after adjusting for other known prognostic factors (HR = 1.25, 95% CI 1.07–1.45, p = 0.004). For the sub-groups of 2365 estrogen receptor (ER) positive patients and 1649 tamoxifen treated patients, FKBPL was significantly associated with BCSS (HR = 1.34, 95% CI 1.13–1.58, p < 0.001, and HR = 1.25, 95% CI 1.04–1.49, p = 0.02, respectively). A univariate analysis revealed that FKBPL was also a significant predictor of relapse free interval (RFI) within the ER positive patient group, but it was only borderline significant within the smaller tamoxifen treated patient group (HR = 1.32 95% CI 1.05–1.65, p = 0.02 and HR = 1.23 95% CI 0.99–1.54, p = 0.06, respectively). The data suggests a role for FKBPL as a prognostic factor for BCSS, with the potential to be routinely evaluated within the clinic.

FKBPL and its peptide derivatives inhibit endocrine therapy resistant cancer stem cells and breast cancer metastasis by downregulating DLL4 and Notch4

“…To date, the mechanism of action has been attributed to a potential role in the CD44 pathway and stabilisation of p21 [5,22,36]. In addition to this, we have shown that high FKBPL levels are associated with a positive prognosis in breast cancer [21]. In this study, for the first time, we assessed the pre-clinical activity of novel systemic anti-cancer therapeutic peptides, ALM201 & AD-01, in the metastatic setting, and highlighted their impact on endocrine therapy resistant cancer stem cells; both areas of unmet clinical need.…”

“…Intracellular FKBPL regulates ER signalling and, as such, has prognostic value in terms of breast cancer survival. This was demonstrated using publically available datasets [21] and in a meta-analysis of five independent breast tissue microarray (TMA) cohorts [21,22]. In this cohort of 3277 patients, FKBPL was a significant and independent predictor of breast cancer specific survival (BCSS), with low FKBPL expression being associated with shorter BCSS (HR = 1.31, 95% CI 1.15-1.50, p < 0.001).…”

“…In this cohort of 3277 patients, FKBPL was a significant and independent predictor of breast cancer specific survival (BCSS), with low FKBPL expression being associated with shorter BCSS (HR = 1.31, 95% CI 1.15-1.50, p < 0.001). Likewise, in a cohort of 2365 ER+ breast cancer patients, low FKBPL expression had also a significantly shorter BCSS compared to high FKBPL expression (HR = 1.34, 95% CI 1.13-1.58, p < 0.001) [21]. Similarly, RBCK1, an E3 ubiquitin-protein ligase, which regulates FKBPL levels, also demonstrated a potential role as a prognostic and predictive biomarker of response to endocrine therapy in breast cancer patients in terms of BCSS [23].…”

“…The anti-CSC activity of AD-01 led to downregulation of stem cell markers, Nanog, Oct4 and Sox2 in breast cancer cell lines while the intratumoural knockdown of FKBPL in a ZR-75 breast cancer xenograft mouse model increased the expression of Nanog/, Oct4 and Sox2 [5]; Sox2 has been implicated in both metastasis and endocrine therapy resistance [28][29][30]. Therefore, since FKBPL and its peptides have demonstrated inhibitory effects on angiogenesis [24,25], CSC signalling [5] and ER signalling [21,22], we hypothesised that FKBPL could also inhibit metastasis and endocrine therapy resistance driven by CSCs in breast cancer. Here, we show for the first time, that FKBPL and its therapeutic peptides reduce metastatic burden in a triple negative breast cancer model and inhibit endocrine therapy resistant CSCs, thereby reducing tumour initiation, in ER+ disease.…”

FKBPL and SIRT-1, key angiogenesis proteins, are downregulated by diabetes in pregnancy

“…In this study, we demonstrated that expression of the key proteins in placental angiogenesis, FKBPL, SIRT-1, PlGF and VEGFR-1, 27,30,[45][46][47] is dysregulated in pregnancies complicated by diabetes. The FKBPL's role in diabetic pregnancies has never been demonstrated previously.…”