Potential Novel Therapy Targets in Neuroendocrine Carcinomas of the Breast

Vranić, Semir; Palazzo, Juan; Sanati, Souzan; Florento, Elena; Contreras, Elma; Xiu, Joanne; Swensen, Jeffrey; Gatalica, Zoran

doi:10.1016/j.clbc.2018.09.001

Cited by 48 publications

(47 citation statements)

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“…Nevertheless, targeting PIK3CA in metastatic NECB could represent an intriguing therapeutic strategy, given the recent results achieved with the use of alpelisib in a population affected from HR positive, HER2 negative advanced breast cancer [ 73 ]. In their recent series, Vranic et al found a TROP-2 protein expression in 21%, suggesting that a small proportion of NEBCs may be sensitive to target therapy with sacituzumab govitecan [ 74 , 75 ]. To date, all currently approved biomarkers of response to immune checkpoint inhibitors (PD-L1 expression, high tumor mutational burden and microsatellite instability status) have proven negative, suggesting that patients with NEBC are not ideal candidates for immunotherapy [ 69 , 74 ] (Table 1 ).…”

Section: Methodsmentioning

confidence: 99%

Neuroendocrine breast carcinoma: a rare but challenging entity

Trevisi

Salvia²,

Lilleri

et al. 2020

Med Oncol

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Breast carcinoma with neuroendocrine differentiation, also known as neuroendocrine breast carcinoma (NEBC), includes a heterogeneous group of rare tumors, which account for 2–5% of all invasive breast carcinomas. Because of their low incidence, most of the current limited knowledge of these tumors derives from anecdotal case reports or small retrospective series. The diagnosis of NEBC is based on the presence of morphological features similar to gastrointestinal and lung NETs and neuroendocrine markers. NEBCs are usually hormone receptors positive and HER2 negative, but despite this luminal phenotype, most recent studies suggested that NEBC could be associated with worse prognosis compared to invasive breast cancer without neuroendocrine differentiation. Due to its rarity and lack of randomized data, there is little evidence to guide the choice of treatment, so NEBC is currently treated as any invasive breast carcinoma not-otherwise specified. Recently, attempts to molecularly characterize NEBC have been made, in order to provide new targets for a more personalized treatment of this uncommon entity.

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Section: Methodsmentioning

confidence: 99%

Neuroendocrine breast carcinoma: a rare but challenging entity

Trevisi

Salvia²,

Lilleri

et al. 2020

Med Oncol

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“…(MLH1, MSH2, MSH6, and PMS2) (clones and thresholds for positivity are provided in Table S1). 4,6,7 Both ER and PR were positive in the majority of cases (8+/9 cases each) ( Table 1). AR was positive in 7/9 cases (78%) without the presence of the ARv7 splice variant.…”

mentioning

confidence: 91%

Novel targetable biomarkers in clear cell carcinoma of the breast uncovered by molecular profiling: A study of nine cases

et al. 2020

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Clear cell differentiation may be occasionally seen in various subtypes of breast cancer, but pure forms of clear cell carcinoma (>90% clear cell morphology) are exceptionally rare. These cancers are characterized by neoplastic cells with an abundant and clear cytoplasm that typically contains glycogen. 1 This type of cancer is considered a distinct cyto-morphological pattern of invasive breast carcinoma of no special type (IBC-NST). 1 The clinical data on clear cell carcinoma are limited and predominantly include small retrospective studies that reported the conflicting results. 2 However, a recent Surveillance, Epidemiology, and End Results (SEER) study revealed that clear cell carcinomas tend to be pathologically high-grade cancers that clinically present at an advanced stage and have poor outcomes. 3 Apart from reports of variable steroid receptor (ER and PR) and HER2 positivity, no studies have systematically explored molecular features and potentially targetable biomarkers in clear cell carcinomas. 2 Herein, we profiled nine pure clear cell carcinomas of the breast using massively parallel DNA and RNA sequencing (NGS), in situ hybridization (ISH), and immunohistochemistry (IHC). All cases were primary mammary clear cell carcinomas that were diagnosed in female patients (mean age: 53.4 years; range: 31-69 years) (Figure 1). Six out of nine cases were periodic acid-Schiff (PAS) positive and PAS-diastase sensitive (glycogen-rich). The NGS platform covered exons from 592 genes (SureSelect XT, Agilent, Santa Clara, CA; and the NextSeq instrument, Illumina, San Diego, CA). The tumor mutational burden (TMB) was considered high if ≥11 mutations/megabase were detected 4 (Table 1). Microsatellite instability (MSI) was calculated from NGS data by direct analysis of short tandem repeat tracts in the target regions of sequenced genes. 5 The ArcherDX FusionPlex Assay (ArcherDX, Boulder, CO) was used for gene fusion assessment (n = 54; Table 1). The following biomarkers were tested by immunohistochemistry (IHC): steroid receptors (ER, PR,

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“…In spite of substantial progresses in breast cancer treatment, detection of novel therapeutic targets for overcoming current obstacles is still required. In recent years, inhibition of cellular and molecular mechanisms that interfere with development of breast cancer is one of the critical diagnostic and therapeutic strategies (1)(2)(3). Nicotinamide phosphoribosyltransferase (NAMPT) is known as the rate-limiting enzyme in the salvage biosyn thetic pathway of nicotinamide adenine dinucleotide (NAD) (4,5) and is considered a critical enzyme that plays important roles in an extensive range of biological activities such as metabolism and immune response.…”

Section: Introductionmentioning

confidence: 99%

Down-regulation of NAMPT expression by miR-154 reduces the viability of breast cancer cells and increases their susceptibility to doxorubicin

Bolandghamtpour¹,

Nourbakhsh²,

Mousavizadeh

et al. 2019

Preprint

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Background Nicotinamide phosphoribosyltransferase (NAMPT) acts as an important enzyme in the salvage pathway of nicotinamide adenine dinucleotide (NAD) biosynthesis. Deregulation of NAD could be associated with progression of many cancers including breast cancer. Here, we evaluated the effect of NAMPT inhibition via miR-154 on survival of breast cancer cells. Methods Breast cancer cell lines including MCF-7 and MDA-MB-231 were transfected with miR-154-5p mimic, inhibitor and their negative controls. Using real-time PCR and western blotting techniques the expression levels of NAMPT and miR-154 were determined and compared with the untreated cells. NAD levels were measured by an enzymatic method. Subsequently, colorimetric methods and flow cytometry were performed to evaluate cell viability and apoptosis. Bioinformatics analyses were performed to investigate whether NAMPT 3′-UTR is a direct target of miR-154 and the findings were confirmed by luciferase reporter assay. Results According to the obtained results, NAMPT 3′-UTR was identified as a direct target of miR-154 and the levels of this miRNA was inversely associated with NAMPT expression both at mRNA and protein levels in breast cancer cell lines. Functionally, miR-154 inhibited the NAD salvage pathway leading to a remarkable decrease in cell survival and induction of apoptosis. Co-treatment of breast cancer cells with doxorubicin and miR-154 mimic significantly reduced cell viability compared to treatment with doxorubicin alone in both cell lines. Conclusions Hence, it was concluded that the inhibition of NAD production by miR-154 might be introduced as a promising therapeutic strategy for the treatment of breast cancer either alone or in combination with other conventional chemotherapeutic agents.

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Potential Novel Therapy Targets in Neuroendocrine Carcinomas of the Breast

Cited by 48 publications

References 50 publications

Neuroendocrine breast carcinoma: a rare but challenging entity

Neuroendocrine breast carcinoma: a rare but challenging entity

Novel targetable biomarkers in clear cell carcinoma of the breast uncovered by molecular profiling: A study of nine cases

Down-regulation of NAMPT expression by miR-154 reduces the viability of breast cancer cells and increases their susceptibility to doxorubicin

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