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Precision medicine based on tumorigenic signaling pathways for triple-negative breast cancer.

ABSTRACT: As a clinically heterogeneous subtype of breast cancer, triple-negative breast cancer (TNBC) is associated with a poor clinical outcome and a high relapse rate. Conventional chemotherapy and radiotherapy are effective treatments for patients with TNBC. However, the prognosis of TNBC remains unsatisfactory. Therefore, a large volume of research has explored the molecular markers and oncogenic signaling pathways associated with TNBC, including the cell cycle, DNA damage response and androgen receptor (AR) signaling pathways, to identify more efficient targeted therapies. However, whether these predicted pathways are effective targets has yet to be confirmed. In the present review, potentially carcinogenic signaling pathways in TNBCs from previous reports were considered, and ultimately five tumorigenic signaling pathways were selected, specifically receptor tyrosine kinases and downstream signaling pathways, the epithelial-to-mesenchymal transition and associated pathways, the immunoregulatory tumor microenvironment, DNA damage repair pathways, and AR and coordinating pathways. The conclusions of the preclinical and clinical trials of each pathway were then consolidated. Although a number of signaling pathways in TNBC have been considered in preclinical and clinical trials, the aforementioned pathways account for the majority of the malignant behaviors of TNBC. Identifying the alterations to different carcinogenic signaling pathways and their association with the heterogeneity of TNBC may facilitate the development of optimal precision medical approaches for patients with TNBC, potentially improving the efficiency of anticancer therapy.

SUBMITTER: Wu N

PROVIDER: S-EPMC6144355 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Precision medicine based on tumorigenic signaling pathways for triple-negative breast cancer.

Wu Nan N Zhang Jinghua J Zhao Jing J Mu Kun K Zhang Jun J Jin Zhao Z Yu Jinpu J Liu Juntian J

Oncology letters 20180810 4

As a clinically heterogeneous subtype of breast cancer, triple-negative breast cancer (TNBC) is associated with a poor clinical outcome and a high relapse rate. Conventional chemotherapy and radiotherapy are effective treatments for patients with TNBC. However, the prognosis of TNBC remains unsatisfactory. Therefore, a large volume of research has explored the molecular markers and oncogenic signaling pathways associated with TNBC, including the cell cycle, DNA damage response and androgen recep ...[more]

PMID: 30250564

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Project description:Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancers with poor prognosis. The etiology of triple-negative breast cancer (TNBC) is involved in various biological signal cascades and multifactorial aberrations of genetic, epigenetic and microenvironment. New therapeutic for TNBC is urgently needed because surgery and chemotherapy are the only available modalities nowadays. A better understanding of the molecular mechanisms would be a great challenge because they are triggered by cascade signaling pathways, genetic and epigenetic regulations, and drug-target interactions. This would allow the design of multi-molecule drugs for the TNBC and non-TNBC. In this study, in terms of systems biology approaches, we proposed a systematic procedure for systems medicine design toward TNBC and non-TNBC. For systems biology approaches, we constructed a candidate genome-wide genetic and epigenetic network (GWGEN) by big databases mining and identified real GWGENs of TNBC and non-TNBC assisting with corresponding microarray data by system identification and model order selection methods. After that, we applied the principal network projection (PNP) approach to obtain the core signaling pathways denoted by KEGG pathway of TNBC and non-TNBC. Comparing core signaling pathways of TNBC and non-TNBC, essential carcinogenic biomarkers resulting in multiple cellular dysfunctions including cell proliferation, autophagy, immune response, apoptosis, metastasis, angiogenesis, epithelial-mesenchymal transition (EMT), and cell differentiation could be found. In order to propose potential candidate drugs for the selected biomarkers, we designed filters considering toxicity and regulation ability. With the proposed systematic procedure, we not only shed a light on the differences between carcinogenetic molecular mechanisms of TNBC and non-TNBC but also efficiently proposed candidate multi-molecule drugs including resveratrol, sirolimus, and prednisolone for TNBC and resveratrol, sirolimus, carbamazepine, and verapamil for non-TNBC.

Project description:Personalised approaches to the management of all solid tumours are increasing rapidly, along with wider accessibility for clinicians. Advances in tumour characterisation and targeted therapies have placed triple-negative breast cancers (TNBC) at the forefront of this approach. TNBC is a highly heterogeneous disease with various histopathological features and is driven by distinct molecular alterations. The ability to tailor individualised and effective treatments for each patient is of particular importance in this group due to the high risk of distant recurrence and death. The mainstay of treatment across all subtypes of TNBC has historically been cytotoxic chemotherapy, which is often associated with off-target tissue toxicity and drug resistance. Neoadjuvant chemotherapy is commonly used as it allows close monitoring of early treatment response and provides valuable prognostic information. Patients who achieve a complete pathological response after neoadjuvant chemotherapy are known to have significantly improved long-term outcomes. Conversely, poor responders face a higher risk of relapse and death. The identification of those subgroups that are more likely to benefit from breakthroughs in the personalised approach is a challenge of the current era where several targeted therapies are available. This review presents an overview of contemporary practice, and promising future trends in the management of early TNBC. Platinum chemotherapy, DNA damage response (DDR) inhibitors, immune checkpoint inhibitors, inhibitors of the PI3K-AKT-mTOR, and androgen receptor (AR) pathways are some of the increasingly studied therapies which will be reviewed. We will also discuss the growing evidence for less-developed agents and predictive biomarkers that are likely to contribute to the forthcoming advances in this field. Finally, we will propose a framework for the personalised management of TNBC based upon the integration of clinico-pathological and molecular features to ensure that long-term outcomes are optimised.

Dataset Information

Precision medicine based on tumorigenic signaling pathways for triple-negative breast cancer.

Publications

Precision medicine based on tumorigenic signaling pathways for triple-negative breast cancer.

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