Expression of mucins (MUC1, MUC2, MUC3, MUC4, MUC5AC and MUC6) and their prognostic significance in human breast cancer

Rakha, Emad A.; Boyce, Richard W G; El-Rehim, Dalia Abd; Kurien, Thomas; Green, Andrew; Paish, Emma C.; Robertson, J. F. R.; Ellis, Ian O.

doi:10.1038/modpathol.3800445

Cited by 306 publications

(302 citation statements)

References 47 publications

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“…Evidence suggests that this overexpression was not due to a gene amplification event, but to an as yet unknown mechanism. MUC1 overexpression is associated with poor prognosis in breast (Rakha et al, 2005) and lung adenocarcinoma (Tsutsumida et al, 2004); however, its influence in the prognosis of mesothelioma has not been reported.…”

Section: Discussionmentioning

confidence: 96%

Overexpression and altered glycosylation of MUC1 in malignant mesothelioma

et al. 2008

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Current interest in the MUC1/EMA mucin relates to its role in malignancy, and its potential as a therapeutic target. MUC1/EMA expression has been observed in the majority of epithelioid mesotheliomas. However, little is known of the characteristics of MUC1/ EMA in mesothelioma. Herein, we studied the cell surface and soluble expression of the MUC1/EMA glycoprotein, and determined the mRNA and genomic expression profiles in mesothelioma. We found that the anti-MUC1 antibody, E29, was the most diagnostically useful of seven antibody clones examined with a sensitivity of 84% (16 out of 19 cases) and no false positive results. MUC1 mRNA expression was significantly higher in mesothelioma samples than in benign mesothelial cells. No amplification of the MUC1 gene was observed by FISH. Seven of 9 mesothelioma samples expressed MUC1-secreted mRNA isoform in addition to the archetypal MUC1/transmembrane form. CA15.3 (soluble MUC1) levels were significantly higher in the serum of mesothelioma patients than in healthy controls but were not significantly different to levels in patients with benign asbestos-related disease. CA15-3 in effusions could differentiate malignant from benign effusions but were not specific for mesothelioma. Thus, as in other cancers, alterations in MUC1 biology occur in mesothelioma and these results suggest that specific MUC1 characteristics may be useful for mesothelioma diagnosis and should also be investigated as a potential therapeutic target.

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Section: Discussionmentioning

confidence: 96%

Overexpression and altered glycosylation of MUC1 in malignant mesothelioma

et al. 2008

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“…S5 A and B). In addition, tumors exposed to the combination of tamoxifen and STA-1474 showed increased differentiation, as monitored by membranous expression of the epithelial marker MUC1, which is typically lost during malignant progression (32) (Fig. S8).…”

Section: Combination Treatment Inhibits the Emergence Of Resistance Inmentioning

confidence: 99%

HSP90 empowers evolution of resistance to hormonal therapy in human breast cancer models

Whitesell

Santagata

Mendillo

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

111

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The efficacy of hormonal therapies for advanced estrogen receptorpositive breast cancers is limited by the nearly inevitable development of acquired resistance. Efforts to block the emergence of resistance have met with limited success, largely because the mechanisms underlying it are so varied and complex. Here, we investigate a new strategy aimed at the very processes by which cancers evolve resistance. From yeast to vertebrates, heat shock protein 90 (HSP90) plays a unique role among molecular chaperones by promoting the evolution of heritable new traits. It does so by regulating the folding of a diverse portfolio of metastable client proteins, many of which mediate adaptive responses that allow organisms to adapt and thrive in the face of diverse challenges, including those posed by drugs. Guided by our previous work in pathogenic fungi, in which very modest HSP90 inhibition impairs resistance to mechanistically diverse antifungals, we examined the effect of similarly modest HSP90 inhibition on the emergence of resistance to antiestrogens in breast cancer models. Even though this degree of inhibition fell below the threshold for proteotoxic activation of the heat-shock response and had no overt anticancer activity on its own, it dramatically impaired the emergence of resistance to hormone antagonists both in cell culture and in mice. Our findings strongly support the clinical testing of combined hormone antagonist-low-level HSP90 inhibitor regimens in the treatment of metastatic estrogen receptor-positive breast cancer. At a broader level, they also provide promising proof of principle for a generalizable strategy to combat the pervasive problem of rapidly emerging resistance to molecularly targeted therapeutics.estrogen receptor | antiestrogen | drug resistance | tumor progression | tamoxifen D rastically limiting the efficacy of targeted therapeutics, the emergence of drug resistance in advanced cancers remains nearly inevitable. From yeast to vertebrates, the molecular chaperone heat shock protein 90 (HSP90) allows organisms to adapt and thrive in the face of diverse challenges, including those posed by drugs and environmental stressors (1, 2). It does so by regulating the folding of a highly diverse portfolio of metastable client proteins, many mediating adaptive responses (3, 4).However, this role for HSP90 in adaptation is greatly magnified by its ability to promote the evolution of heritable new traits. To buffer the proteome against unexpected environmental challenges, HSP90 is present in large excess under normal circumstances. This buffering capacity allows it to modulate the manifestation of preexisting and newly acquired genetic variation within heterogeneous populations of cells, and even whole organisms, thereby dramatically expanding the range of phenotypes on which selection can act (1, 2, 5-7). As a dramatic, therapeutically relevant example, we have shown that this HSP90 buffer enables fungal pathogens spanning ∼1 billion years of evolution to evolve and maintain resistance to every major a...

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“…Mucins are a family of glycoproteins with high molecular weight that have a large number of tandem repeat domains that vary in length. MUC-1 has been found to be expressed abundantly in many epithelial tumors including the majority of breast cancers, 45 and circulating immune complex containing polymorphic epithelial mucin has been detected in breast cancer patients and patients with benign breast tumors. 46,47 An evaluation of the immunogenicity of MUC1, however, identifies a significant potential obstacle in the use of autoantibodies for cancer diagnosis.…”

Section: Autoantibodies In Breast Cancermentioning

confidence: 99%

Humoral Immunity Directed against Tumor-Associated Antigens As Potential Biomarkers for the Early Diagnosis of Cancer

2008

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Over the past decade, it has been demonstrated that cancer is immunogenic, and multiple tumor antigens have been identified in cancer patients. It is now possible to potentially harness the immune response elicited by cancer growth as a potential diagnostic tool. Humoral immunity, or the development of autoantibodies against tumor-associated proteins, may be used as a marker for cancer exposure. Unlike circulating proteins that are shed by bulky tumors, serum autoantibodies are detectable even when antigen expression is minimal. This paper will review the methods used for tumor antigen discovery and overview what is known about autoantibodies targeting common cancer antigens with a focus on breast cancer. Data will be presented modeling the use of tumor antigen associated autoantibodies as a breast cancer diagnostic. The endogenous humoral immune response present in cancer patients may allow the identification of individuals exposed to the malignant transformation of somatic cells.

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Expression of mucins (MUC1, MUC2, MUC3, MUC4, MUC5AC and MUC6) and their prognostic significance in human breast cancer

Cited by 306 publications

References 47 publications

Overexpression and altered glycosylation of MUC1 in malignant mesothelioma

Overexpression and altered glycosylation of MUC1 in malignant mesothelioma

HSP90 empowers evolution of resistance to hormonal therapy in human breast cancer models

Humoral Immunity Directed against Tumor-Associated Antigens As Potential Biomarkers for the Early Diagnosis of Cancer

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