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Article ; Online: In Situ Proximity Ligation Assay to Visualize Protein-Protein Interactions in Tumor Specimens.

Miki, Yasuhiro / Iwabuchi, Erina / Suzuki, Takashi

Methods in molecular biology (Clifton, N.J.)

2023 Volume 2660, Page(s) 123–135

Abstract: Protein-protein interactions (PPI) are the basis of various biological phenomena, such as intracellular signal transduction, gene transcription, and metabolism. PPI are also considered to be involved in the pathogenesis and development of various ... ...

Abstract	Protein-protein interactions (PPI) are the basis of various biological phenomena, such as intracellular signal transduction, gene transcription, and metabolism. PPI are also considered to be involved in the pathogenesis and development of various diseases, including cancer. PPI phenomenon and their functions have been elucidated by gene transfection and molecular detection technologies. On the other hand, in histopathological analysis, although immunohistochemical analyses provide information pertaining to protein expression and their localization in pathophysiological tissues, it has been difficult to visualize the PPI of these proteins. An in situ proximity ligation assay (PLA) was developed as a microscopic visualization technique for PPI in formalin-fixed, paraffin-embedded (FFPE) tissues as well as in cultured cells and frozen tissues. PLA using histopathological specimens enables cohort studies of PPI, which can clarify the significance of PPI in pathology. We have previously shown the dimerization pattern of estrogen receptors and significance of HER2-binding proteins using breast cancer FFPE tissues. In this chapter, we describe a methodology for the visualization of PPI using PLA in pathological specimens.
MeSH term(s)	Female ; Humans ; Breast Neoplasms/metabolism ; Cohort Studies ; Formaldehyde/metabolism ; Paraffin Embedding ; Protein Interaction Mapping/methods ; Protein Interaction Maps ; Receptors, Estrogen/metabolism ; Signal Transduction ; Tissue Fixation/methods ; Fluorescent Dyes ; Antibodies ; Cell Nucleus
Chemical Substances	ERBB2 protein, human (EC 2.7.10.1) ; Formaldehyde (1HG84L3525) ; Receptors, Estrogen ; Fluorescent Dyes ; Antibodies
Language	English
Publishing date	2023-05-16
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-3163-8_9
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Article ; Online: Visualization of the protein-protein interactions of hormone receptors in hormone-dependent cancer research.

Iwabuchi, Erina / Miki, Yasuhiro / Suzuki, Takashi / Sasano, Hironobu

Endocrine oncology (Bristol, England)

2022 Volume 2, Issue 1, Page(s) R132–R142

Abstract: In hormone-dependent cancers, the activation of hormone receptors promotes the progression of cancer cells. Many proteins exert their functions through protein-protein interactions (PPIs). Moreover, in such cancers, hormone-hormone receptor binding, ... ...

Abstract	In hormone-dependent cancers, the activation of hormone receptors promotes the progression of cancer cells. Many proteins exert their functions through protein-protein interactions (PPIs). Moreover, in such cancers, hormone-hormone receptor binding, receptor dimerization, and cofactor mobilization PPIs occur primarily in hormone receptors, including estrogen, progesterone, glucocorticoid, androgen, and mineralocorticoid receptors. The visualization of hormone signaling has been primarily reported by immunohistochemistry using specific antibodies; however, the visualization of PPIs is expected to improve our understanding of hormone signaling and disease pathogenesis. Visualization techniques for PPIs include Förster resonance energy transfer (FRET) and bimolecular fluorescence complementation analysis; however, these techniques require the insertion of probes in the cells for PPI detection. Proximity ligation assay (PLA) is a method that could be used for both formalin-fixed paraffin-embedded (FFPE) tissue as well as immunostaining. It can also visualize hormone receptor localization and post-translational modifications of hormone receptors. This review summarizes the results of recent studies on visualization techniques for PPIs with hormone receptors; these techniques include FRET and PLA. In addition, super-resolution microscopy has been recently reported to be applicable to their visualization in both FFPE tissues and living cells. Super-resolution microscopy in conjunction with PLA and FRET could also contribute to the visualization of PPIs and subsequently provide a better understanding of the pathogenesis of hormone-dependent cancers in the future.
Language	English
Publishing date	2022-10-03
Publishing country	England
Document type	Journal Article ; Review
ISSN	2634-4793
ISSN (online)	2634-4793
DOI	10.1530/EO-22-0059
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Article ; Online: Progesterone receptor-Grb2 interaction is associated with better outcomes in breast cancer.

Wittayavimol, Nattamolphan / Iwabuchi, Erina / Pateetin, Prangwan / Miki, Yasuhiro / Onodera, Yoshiaki / Sasano, Hironobu / Boonyaratanakornkit, Viroj

The Journal of steroid biochemistry and molecular biology

2023 Volume 237, Page(s) 106441

Abstract: In addition to mediating nuclear transcription, PR mediates extranuclear functions mainly through the PR polyproline domain (PPD) interaction with the SH3 domain of cytoplasmic signaling molecules. PR-PPD-SH3 interaction inhibits EGF-mediated signaling ... ...

Abstract	In addition to mediating nuclear transcription, PR mediates extranuclear functions mainly through the PR polyproline domain (PPD) interaction with the SH3 domain of cytoplasmic signaling molecules. PR-PPD-SH3 interaction inhibits EGF-mediated signaling and decreases lung cancer cell proliferation. Grb2 is an essential adaptor molecule with an SH2 domain flanked by two SH3 domains. In this study, we examined whether PR, through interaction between PR-PPD and Grb2-SH3, can interact with Grb2 in cells and breast cancer tissues. Our previous study shows that interaction between PR-PPD and Grb2 could interfere with cytoplasmic signaling and lead to inhibition of EGF-mediated signaling. GST-pulldown analysis shows that PR-PPD specifically interacts with the SH3 domains of Grb2. Immunofluorescence staining shows colocalization of PR and Grb2 in both the nucleus and cytoplasm in BT-474 breast cancer cells. Using Bimolecular Fluorescence Complementation (BiFC) analysis, we show that PR and Grb2 interact in breast cancer cells through the Grb2-SH3 domain. Proximity Ligation Assay (PLA) analysis of 43 breast cancer specimens shows that PR-Grb2 interaction is associated with low histological stage and negatively correlates with lymph node invasion and metastasis in breast cancer. These results, together with our previous findings, suggest that PR-PPD interaction with Grb2 plays an essential role in PR-mediated growth factor signaling inhibition and could contribute significantly to better prognosis in PR- and Grb2-positive breast cancer. Our finding provides a basis for additional studies to explore a novel therapeutic strategy for cancer treatment.
MeSH term(s)	Humans ; Female ; Receptors, Progesterone/genetics ; Breast Neoplasms/genetics ; Epidermal Growth Factor ; Progesterone ; Signal Transduction/physiology ; Protein Binding
Chemical Substances	Receptors, Progesterone ; Epidermal Growth Factor (62229-50-9) ; Progesterone (4G7DS2Q64Y)
Language	English
Publishing date	2023-12-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1049188-0
ISSN	1879-1220 ; 0960-0760
ISSN (online)	1879-1220
ISSN	0960-0760
DOI	10.1016/j.jsbmb.2023.106441
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Article: The Visualization of Protein-Protein Interactions in Breast Cancer: Deployment Study in Pathological Examination.

Iwabuchi, Erina / Miki, Yasuhiro / Sasano, Hironobu

Acta histochemica et cytochemica

2021 Volume 54, Issue 6, Page(s) 177–183

Abstract: The therapeutic strategy is determined by protein expression using immunohistochemistry of estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) in formalin-fixed paraffin-embedded (FFPE) breast cancer tissues. ...

Abstract	The therapeutic strategy is determined by protein expression using immunohistochemistry of estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) in formalin-fixed paraffin-embedded (FFPE) breast cancer tissues. However, few proteins function independently, and many of them functions due to protein-protein interactions (PPIs) with other proteins. Therefore, it is important to focus on PPIs. This review summarizes the PPIs of ER and HER2 in breast cancer, especially those using a proximity ligation assay that can visualize PPIs in FFPE tissues. In particular, assessing the interaction of CEACAM6 with HER2 may serve as a surrogate marker for the efficacy of trastuzumab in patients with breast cancer. Therefore, in this review, the technique used to detect the interaction of CEACAM6 and HER2 in routinely processed pathological specimens will be applied to the clinical practice of drug selection. We showed the possibility as a novel pathological examination method using PPIs.
Language	English
Publishing date	2021-11-18
Publishing country	Japan
Document type	Journal Article ; Review
ZDB-ID	280005-6
ISSN	1347-5800 ; 0044-5991
ISSN (online)	1347-5800
ISSN	0044-5991
DOI	10.1267/ahc.21-00084
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Zs.A 1275: Show issues

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Article: The Pro-Tumorigenic Role of Chemotherapy-Induced Extracellular HSP70 from Breast Cancer Cells via Intratumoral Macrophages.

Yamaguchi-Tanaka, Mio / Takagi, Kiyoshi / Miki, Yasuhiro / Sato, Ai / Iwabuchi, Erina / Miyashita, Minoru / Suzuki, Takashi

Cancers

2023 Volume 15, Issue 6

Abstract: Tumor-associated macrophages (TAMs) contribute to tumor progression and chemoresistance; it is therefore important to clarify the altered functions of macrophages following chemotherapy. While extracellular heat shock protein (HSP) 70 is associated with ... ...

Abstract	Tumor-associated macrophages (TAMs) contribute to tumor progression and chemoresistance; it is therefore important to clarify the altered functions of macrophages following chemotherapy. While extracellular heat shock protein (HSP) 70 is associated with therapeutic resistance, the effects of HSP70 on TAMs remain largely unknown. Here, we conducted in vitro experiments and immunohistochemistry in 116 breast carcinoma specimens to determine whether the secretion of HSP70 from breast cancer cells following chemotherapy affects macrophage function. It was revealed that the interaction of epirubicin (EPI)-exposed breast cancer cells with macrophages enhanced tumor progression, and EPI promoted the secretion of extracellular HSP70 from breast cancer cells. The expression of pro-tumorigenic macrophage marker CD163 was decreased in macrophages treated with a conditioned medium (CM) from HSP70-silenced breast cancer cells. Breast cancer cells treated with CM from HSP70-silenced breast cancer cells showed decreased expression of transforming growth factor (TGF)-β, and the pro-tumorigenic effects of macrophages were impaired when TGF-β signaling was inhibited. Immunohistochemistry demonstrated that HSP70 served as a poor prognostic factor in conjunction with macrophage infiltration. It was therefore concluded that extracellular HSP70 levels increased following chemotherapy and enhanced the pro-tumorigenic effects of TAMs, either directly or indirectly, by regulating TGF-β expression in breast cancer cells.
Language	English
Publishing date	2023-03-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers15061903
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Article ; Online: Intratumoral cortisol associated with aromatase in the endometrial cancer microenvironment.

Miki, Yasuhiro / Iwabuchi, Erina / Takagi, Kiyoshi / Yamazaki, Yuto / Shibuya, Yusuke / Tokunaga, Hideki / Shimada, Muneaki / Suzuki, Takashi / Ito, Kiyoshi

Pathology, research and practice

2023 Volume 251, Page(s) 154873

Abstract: Glucocorticoids bind to glucocorticoid receptors (GR). In the peripheral tissues, active cortisol is produced from inactive cortisone by 11β-hydroxysteroid dehydrogenase (HSD)1. 11β-HSD2 is responsible for this reverse catalysis. Although GR and 11β-HSDs ...

Abstract	Glucocorticoids bind to glucocorticoid receptors (GR). In the peripheral tissues, active cortisol is produced from inactive cortisone by 11β-hydroxysteroid dehydrogenase (HSD)1. 11β-HSD2 is responsible for this reverse catalysis. Although GR and 11β-HSDs have been reported to be involved in the malignant behavior of various cancer types, the concentration of glucocorticoids in cancer tissues has not been investigated. In this study, we measured glucocorticoids in serum and cancer tissues using liquid chromatography-tandem mass spectrometry and clarified, for the first time, the intratumoral "intracrine" production of cortisol by 11β-HSD1/2 in endometrial cancer. Intratumoral cortisol levels were high in the high-malignancy type and the cancer proliferation marker Ki-67-high group, suggesting that cortisol greatly contributes to the malignant behavior of endometrial cancer. A low expression level of the metabolizing enzyme 11β-HSD2 is more important than a high expression level of the synthase 11β-HSD1 for intratumoral cortisol action. Intratumoral cortisol was positively related to the expression/activity of estrogen synthase aromatase, which involved GR expressed in fibroblastic stromal cells but not in cancer cells. Blockade of GR signaling by hormone therapy is expected to benefit patients with endometrial cancer.
MeSH term(s)	Female ; Humans ; 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism ; 11-beta-Hydroxysteroid Dehydrogenase Type 2/metabolism ; Aromatase ; Endometrial Neoplasms ; Glucocorticoids ; Hydrocortisone/metabolism ; Receptors, Glucocorticoid/metabolism ; Tumor Microenvironment
Chemical Substances	11-beta-Hydroxysteroid Dehydrogenase Type 1 (EC 1.1.1.146) ; 11-beta-Hydroxysteroid Dehydrogenase Type 2 (EC 1.1.1.146) ; Aromatase (EC 1.14.14.1) ; Glucocorticoids ; Hydrocortisone (WI4X0X7BPJ) ; Receptors, Glucocorticoid ; CYP19A1 protein, human (EC 1.14.14.1)
Language	English
Publishing date	2023-10-06
Publishing country	Germany
Document type	Journal Article
ZDB-ID	391889-0
ISSN	1618-0631 ; 0344-0338
ISSN (online)	1618-0631
ISSN	0344-0338
DOI	10.1016/j.prp.2023.154873
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Article ; Online: Co-expression of nuclear heterogeneous nuclear ribonucleic protein K and estrogen receptor α in endometrial cancer.

Miki, Yasuhiro / Iwabuchi, Erina / Takagi, Kiyoshi / Suzuki, Takashi / Sasano, Hironobu / Yaegashi, Nobuo / Ito, Kiyoshi

Pathology, research and practice

2022 Volume 231, Page(s) 153795

Abstract: Heterogeneous nuclear ribonucleic protein K (hnRNPK) regulates the expression of various genes, but has contradictory roles as a tumor promoter and a tumor suppressor. We recently reported that the expression of hnRNPK is negatively associated with ... ...

Abstract	Heterogeneous nuclear ribonucleic protein K (hnRNPK) regulates the expression of various genes, but has contradictory roles as a tumor promoter and a tumor suppressor. We recently reported that the expression of hnRNPK is negatively associated with malignant behavior of breast cancer where it was induced by estrogen, and bound to estrogen receptor α (ERα) in the nucleus of breast cancer cells. However, the significance of hnRNPK in endometrial cancer, also an estrogen-dependent cancer, remains unclear. In this study, we first examined the localization of hnRNPK and ERα in normal endometrium and endometrial cancer. hnRNPK and ERα immunoreactivity was detected in the nuclei of endometrial glandular and carcinoma cells. In normal endometria, hnRNPK labeling index/immuno-intensity was significantly higher in the proliferative phase than in the secretory phase. In endometrial cancer tissues, hnRNPK labeling index/immuno-intensity was significantly higher in the adjacent non-malignant glandular cells compared to that in carcinoma cells. Immunohistochemistry results for ERα were identical to that of hnRNPK both in normal endometrium and endometrial cancer. In normal and cancerous tissues, the median value of the hnRNPK labeling index was significantly higher in the ERα-high group. Intratumoral estrogen, but not androgen, measured using liquid chromatography-tandem mass spectrometry, was significantly positively correlated with the hnRNPK labeling index in endometrial cancer tissues. Database analysis revealed that the hnRNPK high expression group had a significantly better prognosis for both overall and disease-free survival. These results suggest that hnRNPK interacts with ERα to regulate endometrial changes during the menstrual cycle and suppress the malignant behavior of endometrial cancer.
MeSH term(s)	Endometrial Neoplasms/diagnosis ; Endometrial Neoplasms/genetics ; Estrogen Receptor alpha/analysis ; Estrogen Receptor alpha/genetics ; Female ; Gene Expression/genetics ; Gene Expression/physiology ; Heterogeneous-Nuclear Ribonucleoprotein K/analysis ; Heterogeneous-Nuclear Ribonucleoprotein K/genetics ; Humans ; Japan
Chemical Substances	Estrogen Receptor alpha ; Heterogeneous-Nuclear Ribonucleoprotein K ; HNRNPK protein, human (146410-60-8)
Language	English
Publishing date	2022-02-03
Publishing country	Germany
Document type	Journal Article
ZDB-ID	391889-0
ISSN	1618-0631 ; 0344-0338
ISSN (online)	1618-0631
ISSN	0344-0338
DOI	10.1016/j.prp.2022.153795
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Article ; Online: SGLT1 as an adverse prognostic factor in invasive ductal carcinoma of the breast.

Tsunokake, Satoko / Iwabuchi, Erina / Miki, Yasuhiro / Kanai, Ayako / Onodera, Yoshiaki / Sasano, Hironobu / Ishida, Takanori / Suzuki, Takashi

Breast cancer research and treatment

2023 Volume 201, Issue 3, Page(s) 499–513

Abstract: Purpose: Sodium/glucose cotransporter (SGLT) 1 and 2 expression in carcinoma cells was recently examined, but their association with the clinicopathological factors of the patients and their biological effects on breast carcinoma cells have remained ... ...

Abstract	Purpose: Sodium/glucose cotransporter (SGLT) 1 and 2 expression in carcinoma cells was recently examined, but their association with the clinicopathological factors of the patients and their biological effects on breast carcinoma cells have remained remain virtually unknown. Therefore, in this study, we explored the expression status of SGLT1 and SGLT2 in breast cancer patients and examined the effects of SGLT1 inhibitors on breast carcinoma cells in vitro. Methods: SGLT1 and SGLT2 were immunolocalized and we first correlated the findings with clinicopathological factors of the patients. We then administered mizagliflozin and KGA-2727, SGLT1 specific inhibitors to MCF-7 and MDA-MB-468 breast carcinoma cell lines, and their growth-inhibitory effects were examined. Protein arrays were then used to further explore their effects on the growth factors. Results: The SGLT1 high group had significantly worse clinical outcome including both overall survival and disease-free survival than low group. SGLT2 status was not significantly correlated with clinical outcome of the patients. Both mizagliflozin and KGA-2727 inhibited the growth of breast cancer cell lines. Of particular interest, mizagliflozin inhibited the proliferation of MCF-7 cells, even under very low glucose conditions. Mizagliflozin downregulated vascular endothelial growth factor receptor 2 phosphorylation. Conclusion: High SGLT1 expression turned out as an adverse clinical prognostic factor in breast cancer patient. This is the first study demonstrating that SGLT1 inhibitors suppressed breast carcinoma cell proliferation. These results indicated that SGLT1 inhibitors could be used as therapeutic agents for breast cancer patients with aggressive biological behaviors.
MeSH term(s)	Humans ; Female ; Sodium-Glucose Transporter 2 Inhibitors/pharmacology ; Sodium-Glucose Transporter 2 Inhibitors/therapeutic use ; Sodium-Glucose Transporter 2/metabolism ; Prognosis ; Vascular Endothelial Growth Factor A/metabolism ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Glucose/metabolism ; Carcinoma, Ductal
Chemical Substances	Sodium-Glucose Transporter 2 Inhibitors ; Sodium-Glucose Transporter 2 ; Vascular Endothelial Growth Factor A ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2023-07-13
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	604563-7
ISSN	1573-7217 ; 0167-6806
ISSN (online)	1573-7217
ISSN	0167-6806
DOI	10.1007/s10549-023-07024-9
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Zs.A 1655: Show issues

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Article ; Online: Heterogeneous Nuclear Ribonucleoprotein K Is Involved in the Estrogen-Signaling Pathway in Breast Cancer.

Iwabuchi, Erina / Miki, Yasuhiro / Suzuki, Takashi / Hirakawa, Hisashi / Ishida, Takanori / Sasano, Hironobu

International journal of molecular sciences

2021 Volume 22, Issue 5

Abstract: Heterogeneous nuclear ribonucleoprotein K (hnRNPK) transcripts are abundant in estrogen receptor (ER)- or progesterone receptor (PR)-positive breast cancer. However, the biological functions of hnRNPK in the ER-mediated signaling pathway have remained ... ...

Abstract	Heterogeneous nuclear ribonucleoprotein K (hnRNPK) transcripts are abundant in estrogen receptor (ER)- or progesterone receptor (PR)-positive breast cancer. However, the biological functions of hnRNPK in the ER-mediated signaling pathway have remained largely unknown. Therefore, this study analyzes the functions of hnRNPK expression in the ER-mediated signaling pathway in breast cancer. We initially evaluated hnRNPK expression upon treatment with estradiol (E2) and ICI 182,780 in the ERα-positive breast carcinoma cell line MCF-7. The results revealed that E2 increased hnRNPK; however, hnRNPK expression was decreased with ICI 182,780 treatment, indicating estrogen dependency. We further evaluated the effects of hnRNPK knockdown in the ER-mediated signaling pathway in MCF-7 cells using small interfering RNAs. The results revealed that hnRNPK knockdown decreased ERα expression and ERα target gene pS2 by E2 treatment. As hnRNPK interacts with several other proteins, we explored the interaction between hnRNPK and ERα, which was demonstrated using immunoprecipitation and proximity ligation assay. Subsequently, we immunolocalized hnRNPK in patients with breast cancer, which revealed that hnRNPK immunoreactivity was significantly higher in ERα-positive carcinoma cells and significantly lower in Ki67-positive or proliferative carcinoma cells. These results indicated that hnRNPK directly interacted with ERα and was involved in the ER-mediated signaling pathway in breast carcinoma. Furthermore, hnRNPK expression could be an additional target of endocrine therapy in patients with ERα-positive breast cancer.
MeSH term(s)	Breast Neoplasms/metabolism ; Carcinoma/metabolism ; Cell Line, Tumor ; Cell Proliferation/physiology ; Estrogens/metabolism ; Female ; Gene Expression Regulation, Neoplastic/physiology ; Heterogeneous-Nuclear Ribonucleoprotein K/metabolism ; Humans ; MCF-7 Cells ; RNA, Small Interfering/metabolism ; Receptors, Estrogen/metabolism ; Signal Transduction/physiology
Chemical Substances	Estrogens ; Heterogeneous-Nuclear Ribonucleoprotein K ; RNA, Small Interfering ; Receptors, Estrogen ; HNRNPK protein, human (146410-60-8)
Language	English
Publishing date	2021-03-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22052581
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Article ; Online: FE65 in breast cancer and its clinicopathological significance.

Xu, Junyao / Iwabuchi, Erina / Miki, Yasuhiro / Kanai, Ayako / Ishida, Takanori / Sasano, Hironobu

Breast cancer (Tokyo, Japan)

2021 Volume 29, Issue 1, Page(s) 144–155

Abstract: Background: Transcription coregulator adapter protein FE65 is well known to play pivotal roles in pathogenesis of Alzheimer's disease by regulating amyloid precursor protein (APP) expression and processing. APP was recently reported to be also involved ... ...

Abstract	Background: Transcription coregulator adapter protein FE65 is well known to play pivotal roles in pathogenesis of Alzheimer's disease by regulating amyloid precursor protein (APP) expression and processing. APP was recently reported to be also involved in development of human malignancies. Therefore, in this study, we studied FE65 status in different subtypes of human breast cancer and correlated the results with cell proliferation and migration of carcinoma cells and clinicopathological features of breast cancer patients to explore its biological and clinical significance in breast cancer. Methods: We first immunolocalized FE65 and APP in 138 breast cancer patients and correlated the results with their tumor grade. Then, we did further exploration by proximity ligation assay, WST-8, and wound-healing assay. Results: FE65 immunoreactivity in carcinoma cells was significantly associated with lymph-node metastasis, ERα, and high pathological N factor. APP immunoreactivity was significantly positively correlated with high pathological N factor. FE65, APP, and p-APP were all significantly correlated with shorter disease-free survival of breast cancer patients. In addition, the status of FE65 was significantly associated with overall survival. Results of in vitro analysis revealed that FE65 promoted the migration and proliferation of T-47D and ZR-75-1 breast carcinoma cells. In situ proximity ligation assay revealed that FE65 could bind to APP in the cytoplasm. FE65 was also associated with APP and ERα in carcinoma cells, suggesting their cooperativity in promoting carcinoma cell proliferation and migration. APP was also significantly associated with adverse clinical outcome of the patients. Conclusions: This is the first study to explore the clinical significance of FE65 in human breast cancer. The significant positive correlation of FE65 with poor clinical outcome, direct binding to APP, and promotion of carcinoma cell proliferation and migration indicated that FE65-APP pathway could serve as the potential candidate of therapeutic intervention in breast cancer patients.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Amyloid beta-Protein Precursor/metabolism ; Breast Neoplasms/metabolism ; Breast Neoplasms/mortality ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Disease-Free Survival ; Estrogen Receptor alpha/metabolism ; Female ; Humans ; Lymphatic Metastasis ; Middle Aged ; Nerve Tissue Proteins/metabolism ; Nuclear Proteins/metabolism
Chemical Substances	APBB1 protein, human ; Amyloid beta-Protein Precursor ; Estrogen Receptor alpha ; Nerve Tissue Proteins ; Nuclear Proteins
Language	English
Publishing date	2021-09-08
Publishing country	Japan
Document type	Journal Article
ZDB-ID	2052429-8
ISSN	1880-4233 ; 1340-6868
ISSN (online)	1880-4233
ISSN	1340-6868
DOI	10.1007/s12282-021-01291-4
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