Molecular mapping the presence of druggable targets in preinvasive and precursor breast lesions: A comprehensive review of biomarkers related to therapeutic interventions

Boyle, David P.; Mullan, Paul B.; Salto-Tellez, Manuel

doi:10.1016/j.bbcan.2013.01.004

Cited by 7 publications

(7 citation statements)

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“…Identifying the key cellular and molecular factors that drive the formation of early breast cancer lesions will ultimately result in the development of preventive approaches for patients that are at high risk for developing invasive breast cancer. Furthermore, as methods for detecting breast lesions become increasingly sensitive, the successful identification of markers associated with early lesions could lead to better prognostic indicators and/or the development of patient-tailored therapies that inhibit malignant progression [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Epiregulin contributes to breast tumorigenesis through regulating matrix metalloproteinase 1 and promoting cell survival

et al. 2015

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BackgroundThe epidermal growth factor (EGF) family of ligands has been implicated in promoting breast cancer initiation, growth and progression. The contributions of EGF family ligands and their receptors to breast cancer are complex, and the specific mechanisms through which different ligands regulate breast tumor initiation and growth are not well-defined. These studies focus on the EGF family member epiregulin (EREG) as a mediator of early stage breast tumorigenesis.MethodsEREG expression levels were assessed in both cell lines and human samples of ductal carcinoma in situ (DCIS) using quantitative RT-PCR, ELISA and immunohistochemistry. Gene knock-down approaches using shRNA-based strategies were used to determine the requirement of EREG for growth of MCF10DCIS cells in vivo, and for identifying mechanisms through which EREG promotes tumor cell survival. Experiments were performed using a combination of two-dimensional culture, three-dimensional culture and tumor growth in vivo.ResultsIn comparison with other EGF family members, EREG was induced in MCF10DCIS cells compared with MCF10A and MCF10AT cells and its expression was partially regulated by fibroblast growth factor receptor (FGFR) activity. Reduced EREG expression in MCF10DCIS cells led to decreased tumor growth in vivo, which was associated with reduced cell survival. Furthermore, treatment of MCF10A cells with exogenous EREG enhanced cell survival both in three-dimensional culture and in response to chemotherapeutic agents. Examination of EREG-induced signaling pathways demonstrated that EREG promoted survival of MCF10A cells through regulating expression of matrix metalloproteinase-1 (MMP-1). To determine the relevance of these findings in human tumors, samples of DCIS were analyzed for EREG and MMP-1 expression. EREG was induced in DCIS lesions compared to normal breast epithelium, and EREG and MMP-1 were correlated in a subset of DCIS samples.ConclusionsTogether, these studies lead to identification of a novel pathway involving EREG and MMP-1 that contributes to the formation of early stage breast cancer. Understanding these complex pathways could ultimately lead to the development of novel biomarkers of neoplastic progression and/or new therapeutic strategies for patients with early stage cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0408-z) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Epiregulin contributes to breast tumorigenesis through regulating matrix metalloproteinase 1 and promoting cell survival

et al. 2015

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“…The antibody Herceptin has had a major impact on treating subtypes that over-express the human epidermal growth factor receptor 2 (HER2) on the cell surface 1, 2. The selective estrogen receptor modulator tamoxifen is currently used for the adjuvant and neo-adjuvant treatment of estrogen receptor (ER) positive luminal breast cancers 3, 4. Despite the implementation of these targeted therapies, drug-resistance and clinical recurrence occur in 30-50% of all women receiving them as primary treatment 5, 6.…”

Section: Introductionmentioning

confidence: 99%

“…TNBC patients respond well to initial anthracycline or taxane-based therapies, but relapse quickly and drug resistance arises 8. A common characteristic of drug resistance is increased cancer aggressiveness and metastatic potential, both factors that lead to poor clinical outcome 4, 9, 10. A major hurdle in the development of new therapeutics for drug-resistant breast cancer is the inability to evaluate therapeutic efficacy in vivo .…”

Section: Introductionmentioning

confidence: 99%

Imaging the Urokinase Plasminongen Activator Receptor in Preclinical Breast Cancer Models of Acquired Drug Resistance

et al. 2014

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Subtype-targeted therapies can have a dramatic impact on improving the quality and quantity of life for women suffering from breast cancer. Despite an initial therapeutic response, cancer recurrence and acquired drug-resistance are commonplace. Non-invasive imaging probes that identify drug-resistant lesions are urgently needed to aid in the development of novel drugs and the effective utilization of established therapies for breast cancer. The protease receptor urokinase plasminogen activator receptor (uPAR) is a target that can be exploited for non-invasive imaging. The expression of uPAR has been associated with phenotypically aggressive breast cancer and acquired drug-resistance. Acquired drug-resistance was modeled in cell lines from two different breast cancer subtypes, the uPAR negative luminal A subtype and the uPAR positive triple negative subtype cell line MDA-MB-231. MCF-7 cells, cultured to be resistant to tamoxifen (MCF-7 TamR), were found to significantly over-express uPAR compared to the parental cell line. uPAR expression was maintained when resistance was modeled in triple-negative breast cancer by generating doxorubicin and paclitaxel resistant MDA-MB-231 cells (MDA-MB-231 DoxR and MDA-MB-231 TaxR). Using the antagonistic uPAR antibody 2G10, uPAR was imaged in vivo by near-infrared (NIR) optical imaging and 111In-single photon emission computed tomography (SPECT). Tumor uptake of the 111In-SPECT probe was high in the three drug-resistant xenografts (> 46 %ID/g) and minimal in uPAR negative xenografts at 72 hours post-injection. This preclinical study demonstrates that uPAR can be targeted for imaging breast cancer models of acquired resistance leading to potential clinical applications.

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“…The expression of each biomarker was assessed in the tumour or normal epithelial component of each region of interest under investigation. The majority of the biomarkers were subjectively scored by semi-quantitative analysis according to standards previously set out in the literature and discussed in a recent review [ 10 ]. Briefly, twelve whole tissue sections for IHC were cut at 4 microns on a rotary microtome, dried at 37°C overnight and then used for IHC assays on Ventana DISCOVERY ® XT or Leica BOND-MAX™ automated immunostainers.…”

Section: Methodsmentioning

confidence: 99%

“…We sought to determine the molecular characteristics of lesions associated with invasive carcinoma in comparison with lesions existing in a pure form (purely non-invasive lesions, or PNL in this manuscript) in terms of established biomarkers and potential druggable targets [ 10 ]. By measuring possible differences in expression, we sought to infer likely co-existence of invasive carcinoma (CEIN) in breast specimens thereby identifying markers of possible prognostic utility.…”

Section: Introductionmentioning

confidence: 99%

Molecular classification of non-invasive breast lesions for personalised therapy and chemoprevention

et al. 2015

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Breast cancer screening has led to a dramatic increase in the detection of pre-invasive breast lesions. While mastectomy is almost guaranteed to treat the disease, more conservative approaches could be as effective if patients can be stratified based on risk of co-existing or recurrent invasive disease.Here we use a range of biomarkers to interrogate and classify purely non-invasive lesions (PNL) and those with co-existing invasive breast cancer (CEIN). Apart from Ductal Carcinoma in situ (DCIS), relative homogeneity is observed. DCIS contained a greater spread of molecular subtypes. Interestingly, high expression of p-mTOR was observed in all PNL with lower expression in DCIS and invasive carcinoma while the opposite expression pattern was observed for TOP2A.Comparing PNL with CEIN, we have identified p53 and Ki67 as predictors of CEIN with a combined PPV and NPV of 90.48% and 43.3% respectively. Furthermore, HER2 expression showed the best concordance between DCIS and its invasive counterpart.We propose that these biomarkers can be used to improve the management of patients with pre-invasive breast lesions following further validation and clinical trials. p53 and Ki67 could be used to stratify patients into low and high-risk groups for co-existing disease. Knowledge of expression of more actionable targets such as HER2 or TOP2A can be used to design chemoprevention or neo-adjuvant strategies. Increased knowledge of the molecular profile of pre-invasive lesions can only serve to enhance our understanding of the disease and, in the era of personalised medicine, bring us closer to improving breast cancer care.

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Molecular mapping the presence of druggable targets in preinvasive and precursor breast lesions: A comprehensive review of biomarkers related to therapeutic interventions

Cited by 7 publications

References 148 publications

Epiregulin contributes to breast tumorigenesis through regulating matrix metalloproteinase 1 and promoting cell survival

Epiregulin contributes to breast tumorigenesis through regulating matrix metalloproteinase 1 and promoting cell survival

Imaging the Urokinase Plasminongen Activator Receptor in Preclinical Breast Cancer Models of Acquired Drug Resistance

Molecular classification of non-invasive breast lesions for personalised therapy and chemoprevention

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