FKBPL Is a Critical Antiangiogenic Regulator of Developmental and Pathological Angiogenesis

Yakkundi, Anita; Bennett, R. Avery; Hernández-Negrete, Ivette; Delalande, Jean-Marie; Hanna, Mary L.; Lyubomska, Oksana; Arthur, Ken; Short, Amy; McKeen, Hayley D.; Nelson, Laura L.; McCrudden, Cian M.; McNally, Ross; McClements, Lana; McCarthy, Helen; Burns, Alan J.; Bicknell, Roy; Kissenpfennig, Adrien; Robson, Tracy

doi:10.1161/atvbaha.114.304539

Cited by 39 publications

(48 citation statements)

References 34 publications

(51 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…FKBPL is emerging as a key player in the DNA damage response [16], steroid receptor signaling [17,18] and more recently, control of tumor growth where it regulates response to endocrine therapy [19] as well as acting as a novel secreted antiangiogenic protein, where it inhibits endothelial cell migration and has potent antitumor activity in vivo [20,21]; this effect is dependent on the cell surface receptor CD44 [22]. More recently, we have demonstrated that because of FKB-PL's ability to target the cell surface receptor, CD44, we are also able to reduce cancer stem cells [23].…”

Section: Introductionmentioning

confidence: 99%

RALA-Mediated Delivery of FKBPL Nucleic Acid Therapeutics

Bennett

Yakkundi

McKeen

et al. 2015

Nanomedicine (Lond.)

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Introductionmentioning

confidence: 99%

RALA-Mediated Delivery of FKBPL Nucleic Acid Therapeutics

Bennett

Yakkundi

McKeen

et al. 2015

Nanomedicine (Lond.)

Self Cite

View full text Add to dashboard Cite

show abstract

“…We have previously demonstrated a role for FKBPL in ER signalling, endocrine therapy response, angiogenesis and CSC differentiation [5,22,24]. 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].…”

Section: Discussionmentioning

confidence: 82%

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

et al. 2019

Self Cite

View full text Add to dashboard Cite

Background: Optimising breast cancer treatment remains a challenge. Resistance to therapy is a major problem in both ER-and ER+ breast cancer. Tumour recurrence after chemotherapy and/or targeted therapy leads to more aggressive tumours with enhanced metastatic ability. Self-renewing cancer stem cells (CSCs) have been implicated in treatment resistance, recurrence and the development of metastatic disease. Methods: In this study, we utilised in vitro, in vivo and ex vivo breast cancer models using ER+ MCF-7 and ER-MDA-MB-231 cells, as well as solid and metastatic breast cancer patient samples, to interrogate the effects of FKBPL and its peptide therapeutics on metastasis, endocrine therapy resistant CSCs and DLL4 and Notch4 expression. The effects of FKBPL overexpression or peptide treatment were assessed using a t-test or one-way ANOVA with Dunnett's multiple comparison test. Results: We demonstrated that FKBPL overexpression or treatment with FKBPL-based therapeutics (AD-01, preclinical peptide /ALM201, clinical peptide) inhibit i) CSCs in both ER+ and ER-breast cancer, ii) cancer metastasis in a triple negative breast cancer metastasis model and iii) endocrine therapy resistant CSCs in ER+ breast cancer, via modulation of the DLL4 and Notch4 protein and/or mRNA expression. AD-01 was effective at reducing triple negative MDA-MB-231 breast cancer cell migration (n ≥ 3, p < 0.05) and invasion (n ≥ 3, p < 0.001) and this was translated in vivo where AD-01 inhibited breast cancer metastasis in MDA-MB-231-lucD3H1 in vivo model (p < 0.05). In ER+ MCF-7 cells and primary breast tumour samples, we demonstrated that ALM201 inhibits endocrine therapy resistant mammospheres, representative of CSC content (n ≥ 3, p < 0.05). Whilst an in vivo limiting dilution assay, using SCID mice, demonstrated that ALM201 alone or in combination with tamoxifen was very effective at delaying tumour recurrence by 12 (p < 0.05) or 21 days (p < 0.001), respectively, by reducing the number of CSCs. The potential mechanism of action, in addition to CD44, involves downregulation of DLL4 and Notch4. Conclusion: This study demonstrates, for the first time, the pre-clinical activity of novel systemic anti-cancer therapeutic peptides, ALM201 and AD-01, in the metastatic setting, and highlights their impact on endocrine therapy resistant CSCs; both areas of unmet clinical need.

show abstract

“…The missense variant rs200847762 is located in the second exon of FKBPL (FK506 binding protein like). The important role of FKBPL in tumorigenesis has been demonstrated by previous studies [22][23][24][25][26][27][28]. FKBPL recruits Hsp90 to regulate the stability of p21 protein, which acts as a regulator of cell cycle progression at G1 [23].…”

Section: Discussionmentioning

confidence: 87%

Low‐frequency nonsynonymous variants in FKBPL and ARPC1B genes are associated with breast cancer risk in Chinese women

Zhou

Jiang

Zhu

et al. 2016

Molecular Carcinogenesis

View full text Add to dashboard Cite

Genome-wide association studies have reported more than 100 independent common loci associated with breast cancer risk. The contribution of low-frequency or rare variants to breast cancer susceptibility has not been well explored. Thus, we applied exome chip to genotype >200 000 low-frequency and rare variants in 1064 breast cancer cases and 1125 cancer-free controls and subsequently validated promising associations in another 1040 breast cancer cases and 1240 controls. We identified two low-frequency nonsynonymous variants at FKBPL (rs200847762, OR = 0.34, 95% CI = 0.20-0.57, P = 4.31 × 10 ) and ARPC1B (rs1045012, OR = 0.56, 95% CI = 0.43-0.74, P = 4.30 × 10 ) associated with breast cancer risk. In stratification analyses, we found that the protective effect of rs200847762 was stronger in ER-positive breast cancer (OR = 0.18, 95% CI = 0.06-0.42) than that in ER-negative one (OR = 0.59, 95% CI = 0.31-1.05). Our findings indicate that low-frequency variants may also contribute to breast cancer susceptibility and genetic variants in 6p21.33 and 7q22.1 are important in breast carcinogenesis. © 2016 Wiley Periodicals, Inc.

show abstract

FKBPL Is a Critical Antiangiogenic Regulator of Developmental and Pathological Angiogenesis

Abstract: Supplemental Digital Content is available in the text.

Cited by 39 publications

References 34 publications

RALA-Mediated Delivery of FKBPL Nucleic Acid Therapeutics

RALA-Mediated Delivery of FKBPL Nucleic Acid Therapeutics

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

Low‐frequency nonsynonymous variants in FKBPL and ARPC1B genes are associated with breast cancer risk in Chinese women

Contact Info

Product

Resources

About