Folate Receptor α Associated With Triple-Negative Breast Cancer and Poor Prognosis

Zhang, Zhang; Wang, Jianmin; Tacha, David; Li, Pamela; Bremer, Ryan; Chen, Huijiao; Wei, Bing; Xiao, Xiuli; Da, Jingjing; Escandón, Joseph M.; Hicks, David G.; Bu, Hong; Tang, Ping

doi:10.5858/arpa.2013-0309-oa

Cited by 118 publications

(90 citation statements)

References 21 publications

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“…The overexpression of FR protein has been confirmed in all clinical breast cancer subtypes, comprised of estrogen receptor-positive (ER+), progesterone receptor-positive (PR+), human epidermal growth factor receptor-positive (HER2+), and triple negative (ER−, HER2−, and PR−) tumors [16][17][18]. Recent polymerase chain reaction studies confirmed that FR is highly expressed in T47D cells [19].…”

Section: Introductionmentioning

confidence: 99%

¹⁷⁷Lu-Dendrimer Conjugated to Folate and Bombesin with Gold Nanoparticles in the Dendritic Cavity: A Potential Theranostic Radiopharmaceutical

Mendoza-Nava

Ferro-Flores

Ramı́rez

et al. 2016

Journal of Nanomaterials

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177 Lu-labeled nanoparticles conjugated to biomolecules have been proposed as a new class of theranostic radiopharmaceuticals. The aim of this research was to synthesize 177 Lu-dendrimer(PAMAM-G4)-folate-bombesin with gold nanoparticles (AuNPs) in the dendritic cavity and to evaluate the radiopharmaceutical potential for targeted radiotherapy and the simultaneous detection of folate receptors (FRs) and gastrin-releasing peptide receptors (GRPRs) overexpressed in breast cancer cells. p-SCN-Benzyl-DOTA was conjugated in aqueous-basic medium to the dendrimer. The carboxylate groups of Lys 1 Lys 3 (DOTA)-bombesin and folic acid were activated with HATU and also conjugated to the dendrimer. The conjugate was mixed with 1% HAuCl 4 followed by the addition of NaBH 4 and purified by ultrafiltration. Elemental analysis (EDS), particle size distribution (DLS), TEM analysis, UV-Vis, and infrared and fluorescence spectroscopies were performed. The conjugate was radiolabeled using 177 LuCl 3 or 68 GaCl 3 and analyzed by radio-HPLC. Studies confirmed the dendrimer functionalization with high radiochemical purity (>95%). Fluorescence results demonstrated that the presence of AuNPs in the dendritic cavity confers useful photophysical properties to the radiopharmaceutical for optical imaging. Preliminary binding studies in T47D breast cancer cells showed a specific cell uptake (41.15 ± 2.72%).177 Ludendrimer(AuNP)-folate-bombesin may be useful as an optical and nuclear imaging agent for breast tumors overexpressing GRPR and FRs, as well as for targeted radiotherapy.

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Section: Introductionmentioning

confidence: 99%

¹⁷⁷Lu-Dendrimer Conjugated to Folate and Bombesin with Gold Nanoparticles in the Dendritic Cavity: A Potential Theranostic Radiopharmaceutical

Mendoza-Nava

Ferro-Flores

Ramı́rez

et al. 2016

Journal of Nanomaterials

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“…A study of breast carcinomas showed FRA protein expression was associated with triplenegative status and high histologic grade. 2 Conversely, a study of endometrial carcinomas showed FRA protein expression was associated with low histologic grade. 4 No relationship between FRA protein expression and histologic grade was observed for ovarian and colorectal carcinomas.…”

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confidence: 99%

Folate Receptor α Expression Level Correlates With Histologic Grade in Lung Adenocarcinoma

Driver

Barrios²,

Ge³

et al. 2015

Archives of Pathology &Amp; Laboratory Medicine

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Context.-Folate receptor a (FRA) is a glycosylphosphatidylinositol-anchored high-affinity folate receptor that localizes to the apical surface of epithelia when it is expressed in normal tissue. Unlike normal tissues, FRA may localize to the basolateral side in tumors. These features make FRA an attractive drug target, and several FRAtargeted drugs have been developed and are in phases of clinical testing. Folate receptor a protein expression shows intertumoral variability that may correlate with response to therapy and to clinicopathologic parameters. Using immunohistochemistry, a recent study of breast carcinomas found FRA protein expression was associated with triple-negative status and high histologic grade in breast cancer. Although a prior study of lung adenocarcinomas found the expression level of the gene encoding FRA, FOLR1, was significantly increased in low-histologic-grade tumors compared to high-histologic-grade tumors, the relationship between FRA protein expression and histologic grade has not been reported for lung adenocarcinomas.Objective.-To investigate the relationship between FRA protein expression level and clinicopathologic parameters in lung adenocarcinomas, including histologic grade, by performing immunohistochemistry for FRA on a cohort of non-small cell lung carcinomas.Design.-High-density tissue microarrays constructed from 188 non-small cell lung carcinomas and used in prior studies were immunostained with FRA-specific antibody clone 26B3. Folate receptor a membranous staining intensity was given a semiquantitative score from 0 to 3þ for triplicate cores of tumor and averaged for each tumor. An average semiquantitative score from 0 to 1.4 was considered low expression, and an average semiquantitative score greater than 1.4 was considered high expression. Conclusions.-Folate receptor a protein was expressed in the majority of lung adenocarcinomas and a minority of lung squamous cell carcinomas. Folate receptor a protein expression correlated with histologic grade for lung adenocarcinomas, and the greatest difference was observed between grade 1 and grade 3. Our results indicate that poorly differentiated adenocarcinomas or focuses of poor differentiation in a heterogeneous tumor may lack FRA protein expression and be more likely to be resistant to FRA-targeting drugs.

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“…This glycosyl-phosphatidylinositol-anchored protein not only serves to bind and transport folate intracellularly, but has also been shown to promote proliferation in cells expressing the receptor, especially in low-folate environments [30]. It has been observed that FRA expression is negatively regulated by ER, and that downregulating ER with antiestrogen agents, such as tamoxifen, increases further FRA expression [22,31], which has also been observed with a poor prognosis [23]. The limited normal tissue distribution of FRA and its overexpression in certain malignancies makes FRA a promising target for directed therapies.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, investigators have examined the prognostic significance of FRA expression in breast carcinoma and found a potential clinical usefulness of FRA overexpression as a prognostic biomarker [21,22,23]. Nonetheless, the utility of FRA as a diagnostic marker of metastatic breast carcinoma in cytology specimens has not been fully established.…”

Section: Introductionmentioning

confidence: 99%

Folate Receptor Alpha Immunohistochemistry in Cytology Specimens of Metastatic Breast Carcinoma

Sheikh

Cohen²,

Siddiqui³

2015

Acta Cytologica

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Background: Folate receptor alpha (FRA) is involved in folate accumulation and utilization, and is expressed in varying proportions in breast, ovary and parotid epithelial cells, among others. FRA overexpression by immunohistochemistry (IHC) has been shown in estrogen/progesterone receptor (ER/PR)-negative carcinoma (40-74%) and in triple-negative breast carcinoma (TNBC; 50-86%) in histological specimens of primary breast cancers. We assessed the feasibility of IHC in detecting FRA expression and its patterns and clinical significance in metastatic TNBC in fine-needle aspiration (FNA) cell blocks (CBs). Materials and Methods: Metastatic breast ductal carcinoma cases were retrospectively immunostained with FRA IHC on FNA CBs. FRA staining was scored qualitatively (+/-), by intensity (0-3) and by staining area (0-100%). Of these metastatic cases, a subset of primary breast carcinoma cases was also immunostained with FRA. The results were correlated with ER, PR and human epidermal growth factor receptor 2 (Her2/Neu) performed by routine IHC. Results: A total of 40 FNA CBs with metastatic disease were studied, including hormone (ER/PR) positive (n = 5), triple positive (n = 5), Her2/Neu-only positive (n = 5) and TNBC (n = 25). FRA IHC showed immunoreactivity with moderate positivity in only 1 (4%) TNBC. All the remaining 39 cases were negative for FRA expression. Five cases of primary TNBC were stained with FRA IHC and were negative for FRA expression. Conclusions: Our data suggest that FRA expression by IHC was rarely associated with ER/PR-negative tumors relative to ER/PR-positive tumors and, more importantly, with TNBC in FNA CBs. This finding may have a clinical significance and prognostic implications in metastatic breast carcinoma. Furthermore, 5 primary TNBC cases did not overexpress FRA by IHC. Hence, antifolate receptor therapies do not appear to be clinically relevant in TNBC based on immunostaining of FNA CBs of metastatic breast cancers.

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Folate Receptor α Associated With Triple-Negative Breast Cancer and Poor Prognosis

Abstract: Our data demonstrate that a significant subgroup of ER/PR-negative and triple-negative breast cancers express FRA, and its expression is associated with worse clinical outcome.

Cited by 118 publications

References 21 publications

¹⁷⁷Lu-Dendrimer Conjugated to Folate and Bombesin with Gold Nanoparticles in the Dendritic Cavity: A Potential Theranostic Radiopharmaceutical

¹⁷⁷Lu-Dendrimer Conjugated to Folate and Bombesin with Gold Nanoparticles in the Dendritic Cavity: A Potential Theranostic Radiopharmaceutical

Folate Receptor α Expression Level Correlates With Histologic Grade in Lung Adenocarcinoma

Folate Receptor Alpha Immunohistochemistry in Cytology Specimens of Metastatic Breast Carcinoma

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Folate Receptor α Associated With Triple-Negative Breast Cancer and Poor Prognosis

Abstract: Our data demonstrate that a significant subgroup of ER/PR-negative and triple-negative breast cancers express FRA, and its expression is associated with worse clinical outcome.

Cited by 118 publications

References 21 publications

177Lu-Dendrimer Conjugated to Folate and Bombesin with Gold Nanoparticles in the Dendritic Cavity: A Potential Theranostic Radiopharmaceutical

177Lu-Dendrimer Conjugated to Folate and Bombesin with Gold Nanoparticles in the Dendritic Cavity: A Potential Theranostic Radiopharmaceutical

Folate Receptor α Expression Level Correlates With Histologic Grade in Lung Adenocarcinoma

Folate Receptor Alpha Immunohistochemistry in Cytology Specimens of Metastatic Breast Carcinoma

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Product

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¹⁷⁷Lu-Dendrimer Conjugated to Folate and Bombesin with Gold Nanoparticles in the Dendritic Cavity: A Potential Theranostic Radiopharmaceutical

¹⁷⁷Lu-Dendrimer Conjugated to Folate and Bombesin with Gold Nanoparticles in the Dendritic Cavity: A Potential Theranostic Radiopharmaceutical