Role of mTORC1 and mTORC2 in Breast Cancer: Therapeutic Targeting of mTOR and Its Partners to Overcome Metastasis and Drug Resistance

Butt, Ghazala; Shahwar, Durray; Qureshi, Muhammad Zahid; Attar, Rukset; Akram, Misbah; Birinci, Yelda; Karatoprak, Gökçe Şeker; Gasparri, Maria Luisa; Farooqı, Ammad Ahmad

doi:10.1007/978-3-030-20301-6_15

Cited by 18 publications

(14 citation statements)

References 29 publications

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“…We also found a subset of genes involved in signaling pathways upregulated in BM1 and BM2 cell sublines, such as mTOR signaling, Myc signaling, protein translation, peptide elongation, mRNA 3'UTR regulation, protein secretion, and cell surface protein targeting to cell membrane, which are consistent with literature that metastatic cancer cells not only showed activation of oncogenic signaling including c-myc/β-catenin signaling and PI3K/AKT/mTOR signaling 25 - 27 , but also showed high levels of secretary or cell surface proteins in expression 10 , involving in cell homing to bone, angiogenesis, invasion, and osteoclast recruitment 10 . Furthermore, based on analysis of multiple publicly available datasets, a positive association between the gene sets representing protein translation and metastasis in basal-like breast cancer has been reported 28 .…”

Section: Discussionsupporting

confidence: 91%

Cancer stem cell property and gene signature in bone-metastatic Breast Cancer cells

Luo¹,

Xu²,

Li³

et al. 2020

Int. J. Biol. Sci.

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The majority of the deaths from breast cancer is due to metastasis. Bone is the most common organ to which breast cancer cells metastasize. The mechanism regulating the bone-metastatic preference remains unclear; there is a lack of a gene signature to distinguish bone-metastatic breast cancer cells. Herein, florescence-labeled MDA-MB-231 cells were transplanted into the fat pads of of the mammary gland in nude mice to generate breast tumors. Tumor cells invaded into the circulation were tracked by in vivo flow cytometry system. Metastatic tumor cells in the bone were isolated using fluorescent-activated cell sorting technique, followed by assays of cell colony formation, migration and invasion, mammosphere formation in vitro, mammary gland tumorigenesis in vivo, and Next-Generation Sequencing analysis as well. Through tumor regeneration and cell sorting, two bone-metastatic cell sublines were derived from MDA-MB-231 cells; which showed higher abilities to proliferate, migrate, invade and epithelial-to-mesenchymal transit in vitro, and stronger ability to regenerate tumors and metastasize to the bone in vivo. Both cell sublines exhibited cancer stem cell-like characteristics including higher expression levels of stem cell markers and stronger ability for mommaspheres formation. Furthermore, a Normal Distribution-like pattern of the bone-metastatic cells invading into circulation was firstly identified. Deep-sequencing analysis indicated upregulation of multiple signaling pathways in regulating EMT, cell membrane budding and morphologic change, lipid metabolism, and protein translation, which are required to provide adequate metabolic enzymes, structural proteins, and energy for the cells undergoing metastasis. In conclusion, we established two bone-metastatic breast cancer cell sublines, carrying higher degree of stemness and malignancy. The gene signature distinguishing the bone-metastatic breast cancer cells holds therapeutic potentials in prevention of breast cancer metastasis to the bone.

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Section: Discussionsupporting

confidence: 91%

Cancer stem cell property and gene signature in bone-metastatic Breast Cancer cells

Luo¹,

Xu²,

Li³

et al. 2020

Int. J. Biol. Sci.

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“…Dysregulation of the spatiotemporally controlled mTOR-driven pathway contributes to breast cancer development, progression, and drug resistance (Butt et al, 2019;Guerrero-Zotano et al, 2016). Targeting PI3K/AKT/mTOR-mediated autophagy is important for increasing the chemosensitivity of tumor cells and preventing drug resistance (Xu et al, 2020).…”

Section: Linc-ror Promotes Cell Proliferation Migration and Invasiomentioning

confidence: 99%

Linc‐ROR promotes the progression of breast cancer and decreases the sensitivity to rapamycin through miR‐194‐3p targeting MECP2

et al. 2020

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linc‐ROR is reported to be a potential biomarker of breast cancer, but the detailed mechanism of linc‐ROR‐mediated breast cancer regulation has not been fully studied. We aimed to explore how linc‐ROR affects proliferation, metastasis, and drug sensitivity in breast cancer. Cell lines in which linc‐ROR was overexpressed or knocked down were constructed, and the cell proliferation, colony formation, cell migration, and invasion abilities of these lines were explored. A CCK‐8 assay was performed to determine the sensitivity of the breast cancer cells to rapamycin. Next‐generation sequencing was conducted to explore the detailed regulatory mechanism of linc‐ROR; differentially expressed RNAs in the linc‐ROR‐overexpressing cell line compared with the negative control were screened out, and their target genes were chosen to perform Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes analysis, protein–protein interaction network analysis, and competing endogenous RNA (ceRNA) network analysis. The ceRNA mechanism of linc‐ROR for miR‐194‐3p, which targets MECP2, was determined through dual‐luciferase reporter assay, RT–qPCR, western blot, and rescue experiments. Finally, we found that linc‐ROR was upregulated in breast tumor tissues. linc‐ROR promoted the cell proliferation, colony formation, cell migration, and invasion of breast cancer and decreased the sensitivity of breast cancer cells to rapamycin. The overexpression of linc‐ROR triggered changes in the whole transcriptome of breast cancer cells, and a total of 85 lncRNAs, 414 microRNAs, 490 mRNAs, and 92 circRNAs were differentially expressed in the linc‐ROR‐overexpressing cell line compared with the negative control. Through a series of bioinformatic analyses, the ‘linc‐ROR/miR‐194‐3p/MECP2’ ceRNA regulatory axis was confirmed to be involved in the linc‐ROR‐mediated progression and drug sensitivity of breast cancer. In conclusion, linc‐ROR serves as an onco‐lncRNA in breast cancer and promotes the survival of breast cancer cells during rapamycin treatment by functioning as a ceRNA sponge for miR‐194‐3p, which targets MECP2.

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“…7K). Considering that mTORC1 signaling activation has been shown to promote therapy resistance in BC [17,18], these data suggested that MSMO1 could promote drug resistance through modulating the mTORC1 signaling pathways in BC cells.…”

Section: Plasma Exmsmo1 As Predictive Biomarker For Neoadjuvant Chemomentioning

confidence: 92%

Plasma Extracellular Vesicle Long RNA Profiles in the Diagnosis and Prediction of Treatment Response for Breast Cancer

Zhao

Guo

et al. 2020

Preprint

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Background: The utility of extracellular vesicle long RNAs (exLRs) as noninvasive biomarkers in breast cancer remains elusive. The purpose of this study was to explore the potential of exLRs as clinically actionable biomarkers for breast cancer diagnosis, classification, and neoadjuvant therapy efficacy prediction. Methods: One hundred and seventy-two participants, including 112 breast cancer patients, 19 benign patients and 41 healthy controls, were enrolled in this case-control study. The exLR profile of the plasma samples was analyzed by exLR sequencing. The d-signature was identified using a support vector machine algorithm with a training cohort (n=120) and was validated using an internal validation cohort (n=52). Treatment efficacy prediction was conducted with 48 patients who received neoadjuvant chemotherapy.Results: We constructed a breast cancer diagnostic signature that showed high accuracy with an area under the curve (AUC) of 0.960 in the training cohort and 0.900 in the validation cohort. The signature was able to identify early stage BC (I/II) with an AUC of 0.940. Integrating the signature could increase the diagnosis accuracy by up to 91.9% for breast cancer patients with the corresponding predictive results based on the Breast Imaging Reporting and Data System classification of 4 or 5. Moreover, the exLRs could provide a strong indication of the breast cancer subtypes, and exMSMO1 is employable as a predictive biomarker in response to neoadjuvant chemotherapy.Conclusions: This study demonstrated the value of exLR profiling to provide potential biomarkers for early detection and treatment efficacy prediction of breast cancer.

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Role of mTORC1 and mTORC2 in Breast Cancer: Therapeutic Targeting of mTOR and Its Partners to Overcome Metastasis and Drug Resistance

Cited by 18 publications

References 29 publications

Cancer stem cell property and gene signature in bone-metastatic Breast Cancer cells

Cancer stem cell property and gene signature in bone-metastatic Breast Cancer cells

Linc‐ROR promotes the progression of breast cancer and decreases the sensitivity to rapamycin through miR‐194‐3p targeting MECP2

Plasma Extracellular Vesicle Long RNA Profiles in the Diagnosis and Prediction of Treatment Response for Breast Cancer

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