Diagnostic accuracy of small breast epithelial mucin mRNA as a marker for bone marrow micrometastasis in breast cancer: a pilot study

Valladares‐Ayerbes, Manuel; Iglesias-Díaz, Pilar; Díaz‐Prado, Silvia; Ayude, Daniel; Medina, Vanessa; Haz, Mar; Reboredo, Margarita; Antolín, Silvia; Calvo, Lourdes; Antón-Aparicio, Luis

doi:10.1007/s00432-009-0559-7

Cited by 19 publications

(15 citation statements)

References 39 publications

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“…In our study, increased miR-21 level was found in 90.6% of tumors, consistently with previous studies investigating patients with colon (25,27,39), gastric (21,39,45,46) and pancreatic (22,23,29) adenocarcinomas. However, we did not find any significant associations between miR-21 level and the clinical and pathologic characteristics, in line with recently reported results (47).…”

Section: Discussionsupporting

confidence: 93%

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Prognostic impact of disseminated tumor cells and microRNA-17-92 cluster deregulation in gastrointestinal cancer

Valladares‐Ayerbes

Blanco²,

Haz³

et al. 2011

Int J Oncol

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Abstract. The presence of tumor cells in the bone marrow (BM) could be relevant to identifying high risk of disease progression and death in gastrointestinal cancer. However, the molecular profile associated with disseminated tumor cells (DTCs) homing to the BM has yet to be defined. MicroRNAs (miRNA) play key roles in cellular processes implicated in cancer. Thus, we investigated in 38 patients with colorectal, gastric or pancreatic cancer whether the presence of BM-DTCs is associated with a specific miRNA tumor profile and analyzed their potential prognostic impact. DTCs were detected by immunocytochemistry and anti-cytokeratin antibodies in 42.1% of the patients. miRNAs were isolated from formalin-fixed, paraffin-embedded tumors. qRT-PCR was used for miRNA profiling. No significant associations were found among DTC detection and miRNA deregulation. Kaplan-Meier curves demonstrated significantly reduced progression-free survival (PFS) and overall survival (OS) in the DTC-positive patients. Although miR-21 was upregulated in 90.6% of the tumors, no associations with outcomes were found. miR-17 and miR-20a (miRNA-17-92 cluster) were upregulated in 33.3 and 42.4%, respectively. Upregulation of both was correlated and found in 30.3%. Univariate analysis shows that increasing values for miR-20a were significantly associated with reduced PFS (HR 1.022; p=0.016) and OS (HR 1.027; p=0.003). In multivariate Cox models, DTC positivity (HR 4.07; p=0.005) and miR-17 overexpression (HR 2.11; p=0.003) were significantly associated with a higher risk of disease progression. The presence of DTCs in the BM (HR 3.98; p=0.010) and a miR-17 overexpression (HR 2.62; p<0.001) were also associated with a risk of death. Our study suggests that the presence of BM-DTCs and the upregulation of the miR-17-92 cluster in tumors are both significant but independent prognostic markers in gastrointestinal cancer patients.

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Section: Discussionsupporting

confidence: 93%

“…Immunocytochemistry (ICC) was performed as described previously (27) using the Vectastain ABC-AP kit (Vector), according to the manufacturer's instructions. Slides (5x10 5 BM MNCs) were incubated with the anti-cytokeratin (CK) monoclonal antibodies AE1/AE3 (Dako).…”

Section: Methodsmentioning

confidence: 99%

Prognostic impact of disseminated tumor cells and microRNA-17-92 cluster deregulation in gastrointestinal cancer

Valladares‐Ayerbes

Blanco²,

Haz³

et al. 2011

Int J Oncol

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“…7, 8, 9, 10 Its limited normal tissue expression also renders MUCL1 an attractive tumor-associated antigen for targeted therapy of breast cancers. Despite our understanding of the expression of MUCL1 in breast cancer, the cellular localization of the MUCL1 protein has remained largely unstudied, which will have a major impact on drug developmentability.…”

Section: Introductionmentioning

confidence: 99%

HER2 drives Mucin-like 1 to control proliferation in breast cancer cells

Conley¹,

Bosco²,

Tice³

et al. 2016

Oncogene

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Mucin-like 1 (MUCL1) was first identified as a breast-specific gene over a decade ago. Based on its highly restricted mRNA expression in breast tissue and continued expression during breast tumorigenesis and progression, MUCL1 is an attractive tumor-associated antigen and a potential therapeutic target. However, very little is known about the cellular location, biological functions and regulation of the MUCL1 protein, which will have a major impact on its druggability. Here we describe our efforts to fully characterize the cellular localization of MUCL1, investigate its regulation by key breast cancer oncogenes such as human epidermal growth factor receptor 2 (HER2) and discover its functional roles in breast cancer. Although some mucins are membrane bound, our data indicate that MUCL1 is secreted by some breast cancer cells, whereas others only express high levels of intracellular MUCL1. MUCL1 expression is highest in HER2-amplified breast tumors and inhibiting HER2 activity in tumor cells resulted in a decreased MUCL1 expression. In-depth investigation demonstrated that phosphoinositide3-kinase/Akt pathway, but not Ras/MEK pathway, controls MUCL1 expression downstream of HER2. Phenotypic assays revealed a strong dependence of HER2-positive cells on MUCL1 for cell proliferation. We further identified the mechanism by which MUCL1 regulates cell growth. Knockdown of MUCL1 induced a G1/S phase arrest concomitant with decreased cyclin D and increased p21 and p27 levels. Finally, we investigated the impact of MUCL1 loss on kinase signaling pathways in breast cancer cells through phospho-kinase array profiling. MUCL1 silencing abrogated phospho-focal adhesion kinase (FAK), Jun NH2-terminal kinase (JNK) and c-Jun signals, but not extracellular signal-regulated kinase or Akt pathway activities, thereby pointing to FAK/JNK pathway as the downstream effector of MUCL1 signaling. We are the first to identify an important role for MUCL1 in the proliferation of breast cancer cells, probably mediated via the FAK/JNK signaling pathway. Taken together, these data suggest a potential utility for therapeutic targeting of this protein in breast cancer.

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“…SBEM is identified as a putative breast-specific gene and considered to be a promising breast specific marker [9]. Although published studies have suggested that SBEM might represent a suitable marker for molecular detection of isolated tumor cells in bone marrow and targeting bone marrow micrometastasis in breast cancer patients [10,11], thus far, there has been no report on whether the expression of SBEM is a predictor for hematogenous micrometastasis and response to neoadjuvant chemotherapy in breast cancer.…”

Section: Introductionmentioning

confidence: 99%

Small breast epithelial mucin (SBEM) has the potential to be a marker for predicting hematogenous micrometastasis and response to neoadjuvant chemotherapy in breast cancer

Liu

Xie

et al. 2010

Clin Exp Metastasis

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To investigate the potential role of small breast epithelial mucin (SBEM) as a marker for detecting hematogenous micrometastasis in breast cancer and explore its clinical significance in neoadjuvant chemotherapy. SBEM protein expression in 82 tissue specimens of primary breast cancer was detected using immunohistochemistry (IHC), and SBEM expression in peripheral blood (PB) samples of 109 primary breast cancer patients (94 cases at stage I-III, 15 cases at stage IV) was detected by flow cytometry (FCM) and reverse transcription polymerase chain reaction (RT-PCR). Moreover, SBEM mRNA expression was monitored by quantification real-time PCR (QPCR) before and after 3 cycles' neoadjuvant chemotherapy. SBEM expression correlated with tumor node metastasis (TNM) staging and lymph node metastasis at both mRNA and protein levels. SBEM expression in PB of breast cancer patients was markedly higher than that of healthy donors and other cancer patients. SBEM was found expressed in PB of 50 cases among 94 cases at stage I-III and expressed in PB of 11 cases among 15 cases at stage IV. After 3 cycles' neoadjuvant chemotherapy, SBEM expression levels were significantly down-regulated in up to 58% breast cancer patients. SBEM has the potential to be a specific marker for predicting hematogenous micrometastasis and response to neoadjuvant chemotherapy in breast cancer.

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Diagnostic accuracy of small breast epithelial mucin mRNA as a marker for bone marrow micrometastasis in breast cancer: a pilot study

Abstract: SBEM might represent a suitable marker for molecular detection of ITCs in BM in breast cancer patients. Analysis of prognostic value for SBEM mRNA-based assay should take into account the heterogeneity and different molecular subtypes of breast cancer.

Cited by 19 publications

References 39 publications

Prognostic impact of disseminated tumor cells and microRNA-17-92 cluster deregulation in gastrointestinal cancer

Prognostic impact of disseminated tumor cells and microRNA-17-92 cluster deregulation in gastrointestinal cancer

HER2 drives Mucin-like 1 to control proliferation in breast cancer cells

Small breast epithelial mucin (SBEM) has the potential to be a marker for predicting hematogenous micrometastasis and response to neoadjuvant chemotherapy in breast cancer

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