Stromal Clusterin Expression Predicts Therapeutic Response to Neoadjuvant Chemotherapy in Triple Negative Breast Cancer

Wang, Yihong; Brodsky, Alexander S.; Xiong, Jinjun; Lopresti, Mary Lorraine; Yang, Dongfang; Resnick, Murray B.

doi:10.1016/j.clbc.2017.08.007

Cited by 13 publications

(13 citation statements)

References 43 publications

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“…29 Meanwhile, we also used the stromal cell abundance for prediction in TNBC patients and got an AUC = 0.55, indicating a predictive role of stromal cells in TNBC patients' NCT response ( Figure S3E-F). [69][70][71][72] Therefore, our findings provide an understanding of cancer biology in breast cancer by showing which aspect(s) of the tumor microenvironment might influence the response to the NCT.…”

Section: Discussionmentioning

confidence: 82%

Gene signature‐based prediction of triple‐negative breast cancer patient response to Neoadjuvant chemotherapy

2020

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Neoadjuvant chemotherapy is the current standard of care for large, advanced, and/or inoperable tumors, including triple‐negative breast cancer. Although the clinical benefits of neoadjuvant chemotherapy have been illustrated through numerous clinical trials, more than half of the patients do not experience therapeutic benefit and needlessly suffer from side effects. Currently, no clinically applicable biomarkers are available for predicting neoadjuvant chemotherapy response in triple‐negative breast cancer; the discovery of such a predictive biomarker or marker profile is an unmet need. In this study, we introduce a generic computational framework to calculate a response‐probability score (RPS), based on patient transcriptomic profiles, to predict their response to neoadjuvant chemotherapy. We first validated this framework in ER‐positive breast cancer patients and showed that it predicted neoadjuvant chemotherapy response with equal performance to several clinically used gene signatures, including Oncotype DX and MammaPrint. Then, we applied this framework to triple‐negative breast cancer data and, for each patient, we calculated a response probability score (TNBC‐RPS). Our results indicate that the TNBC‐RPS achieved the highest accuracy for predicting neoadjuvant chemotherapy response compared to previously proposed 143 gene signatures. When combined with additional clinical factors, the TNBC‐RPS achieved a high prediction accuracy for triple‐negative breast cancer patients, which was comparable to the prediction accuracy of Oncotype DX and MammaPrint in ER‐positive patients. In conclusion, the TNBC‐RPS accurately predicts neoadjuvant chemotherapy response in triple‐negative breast cancer patients and has the potential to be clinically used to aid physicians in stratifying patients for more effective neoadjuvant chemotherapy.

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Section: Discussionmentioning

confidence: 82%

Gene signature‐based prediction of triple‐negative breast cancer patient response to Neoadjuvant chemotherapy

2020

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“…We demonstrated that the molecular mechanism by which BM-derived CAFs promote angiogenesis is mediated by up-regulation of the secreted glycoprotein Clusterin, shown to affect tumor cell growth, angiogenesis, and resistance to therapy (Fu et al, 2013; Koltai, 2014; Tellez et al, 2016; Wang et al, 2018). Moreover, Clusterin was found to be up-regulated in human breast cancer, in correlation with tumor progression (Redondo et al, 2000; Yom et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Bone marrow–derived fibroblasts are a functionally distinct stromal cell population in breast cancer

Raz

Cohen

Shani

et al. 2018

Journal of Experimental Medicine

199

216

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Cancer-associated fibroblasts (CAFs) are highly prominent in breast tumors, but their functional heterogeneity and origin are still largely unresolved. We report that bone marrow (BM)–derived mesenchymal stromal cells (MSCs) are recruited to primary breast tumors and to lung metastases and differentiate to a distinct subpopulation of CAFs. We show that BM-derived CAFs are functionally important for tumor growth and enhance angiogenesis via up-regulation of Clusterin. Using newly generated transgenic mice and adoptive BM transplantations, we demonstrate that BM-derived fibroblasts are a substantial source of CAFs in the tumor microenvironment. Unlike resident CAFs, BM-derived CAFs do not express PDGFRα, and their recruitment resulted in a decrease in the percentage of PDGFRα-expressing CAFs. Strikingly, decrease in PDGFRα in breast cancer patients was associated with worse prognosis, suggesting that BM-derived CAFs may have deleterious effects on survival. Therefore, PDGFRα expression distinguishes two functionally unique CAF populations in breast tumors and metastases and may have important implications for patient stratification and precision therapeutics.

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“…In prostate, breast, and colon cancer, the expression of CLU changes with disease progression both in the epithelial cancer cells and in the surrounding stromal tissue [ 151 , 152 , 153 ]. Of note, only clusterin stromal staining significantly correlates with disease recurrence and clinical outcome following surgical intervention or chemotherapy [ 153 , 154 ].…”

Section: Extracellular Chaperones In the Tme: Focus On Their Roles In Cancer-related Inflammation And Ecm Remodelingmentioning

confidence: 99%

Inflammation, Extracellular Matrix Remodeling, and Proteostasis in Tumor Microenvironment

Marozzi

Parnigoni

Negri

et al. 2021

IJMS

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Cancer is a multifaceted and complex pathology characterized by uncontrolled cell proliferation and decreased apoptosis. Most cancers are recognized by an inflammatory environment rich in a myriad of factors produced by immune infiltrate cells that induce host cells to differentiate and to produce a matrix that is more favorable to tumor cells’ survival and metastasis. As a result, the extracellular matrix (ECM) is changed in terms of macromolecules content, degrading enzymes, and proteins. Altered ECM components, derived from remodeling processes, interact with a variety of surface receptors triggering intracellular signaling that, in turn, cancer cells exploit to their own benefit. This review aims to present the role of different aspects of ECM components in the tumor microenvironment. Particularly, we highlight the effect of pro- and inflammatory factors on ECM degrading enzymes, such as metalloproteases, and in a more detailed manner on hyaluronan metabolism and the signaling pathways triggered by the binding of hyaluronan with its receptors. In addition, we sought to explore the role of extracellular chaperones, especially of clusterin which is one of the most prominent in the extracellular space, in proteostasis and signaling transduction in the tumor microenvironment. Although the described tumor microenvironment components have different biological roles, they may engage common signaling pathways that favor tumor growth and metastasis.

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Stromal Clusterin Expression Predicts Therapeutic Response to Neoadjuvant Chemotherapy in Triple Negative Breast Cancer

Cited by 13 publications

References 43 publications

Gene signature‐based prediction of triple‐negative breast cancer patient response to Neoadjuvant chemotherapy

Gene signature‐based prediction of triple‐negative breast cancer patient response to Neoadjuvant chemotherapy

Bone marrow–derived fibroblasts are a functionally distinct stromal cell population in breast cancer

Inflammation, Extracellular Matrix Remodeling, and Proteostasis in Tumor Microenvironment

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