The Epithelial-to-Mesenchymal Transition and Cancer Stem Cells: A Coalition Against Cancer Therapies

Hollier, Brett G.; Evans, Kurt W.; Mani, Sendurai A.

doi:10.1007/s10911-009-9110-3

Cited by 317 publications

(288 citation statements)

References 131 publications

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“…Although breast CSCs may arise as the result of EMT (Mani et al, 2008;Hollier et al, 2009;Wellner et al, 2009;Kong et al, 2010;Singh and Settleman, 2010), the current findings support the notion that this intrinsic epithelial plasticity of cancer cells can also be exploited to inhibit their invasiveness and metastatic potential by using selected BMPs. It provides the rationale for the clinical development of differentiation-inducing compounds as a novel strategy to target CSCs or their supportive microenvironment in advanced breast cancer.…”

Section: Bmp2/7 Inhibits the Breast Cancer Stem Cell Subpopulation Jtsupporting

confidence: 76%

The BMP2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation

et al. 2011

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Accumulating evidence suggests that a subpopulation of breast cancer cells, referred to as cancer stem cells (CSCs), have the ability to propagate a tumor and potentially seed new metastases. Furthermore, stimulation of an epithelialto-mesenchymal transition by factors like transforming growth factor-b (TGFb) is accompanied with the generation of breast CSCs. Previous observations indicated that bone morphogenetic protein-7 (BMP7) antagonizes the protumorigenic and prometastatic actions of TGFb, but whether BMP7 action is mechanistically linked to breast CSCs has remained elusive. Here, we have studied the effects of BMP7, BMP2 and a BMP2/7 heterodimer on the formation of human breast CSCs (ALDH hi /CD44 hi / CD24 À/low ) and bone metastases formation in a preclinical model of intra-cardiac injection of MDA-MB-231 cells in athymic nude (Balb/c nu/nu) mice. The BMP2/7 heterodimer was the most efficient stimulator of BMP signaling and very effectively reduced TGFb-driven Smad signaling and cancer cell invasiveness. The tested BMPs-particularly the heterodimeric BMP2/7-strongly reduced the size of the ALDH hi /CD44 hi /CD24 À/low CSC subpopulation. In keeping with these in vitro observations, pretreatment of cancer cells with BMPs for 72 h prior to systemic inoculation of the cancer cells inhibited the formation of bone metastases. Collectively, our data support the notion that breast CSCs are involved in bone metastasis formation and describe heterodimeric BMP2/7 as a powerful TGFb antagonist with anti-metastatic potency.

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Section: Bmp2/7 Inhibits the Breast Cancer Stem Cell Subpopulation Jtsupporting

confidence: 76%

The BMP2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation

et al. 2011

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“…The link between the inflammatory NFB pathway and breast cancer is also supported by the fact that a deregulated, or constitutively active, NFB pathway is associated with aggressive breast cancer phenotypes and therapy resistance (5-9). More recently, activation of the NFB pathway has been shown to regulate the survival and propagation of breast cancer stem cells (CSCs) (10 -12), which are a small subset of tumor cells that evade all standard therapies and are involved in metastasis and tumor recurrence (13)(14)(15)(16)(17)(18). Given that the NFB pathway is essential for breast cancer progression and aggressiveness, its inhibition can be exploited to eradicate CSCs and other detrimental NFB-dependent tumor phenotypes.…”

mentioning

confidence: 99%

Dimethyl Fumarate Inhibits the Nuclear Factor κB Pathway in Breast Cancer Cells by Covalent Modification of p65 Protein

Kastrati

Siklos

Calderon-Gierszal

et al. 2016

Journal of Biological Chemistry

114

102

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In breast tumors, activation of the nuclear factor B (NFB) pathway promotes survival, migration, invasion, angiogenesis, stem cell-like properties, and resistance to therapy-all phenotypes of aggressive disease where therapy options remain limited. Adding an anti-inflammatory/anti-NFB agent to breast cancer treatment would be beneficial, but no such drug is approved as either a monotherapy or adjuvant therapy. To address this need, we examined whether dimethyl fumarate (DMF), an anti-inflammatory drug already in clinical use for multiple sclerosis, can inhibit the NFB pathway. We found that DMF effectively blocks NFB activity in multiple breast cancer cell lines and abrogates NFB-dependent mammosphere formation, indicating that DMF has anti-cancer stem cell properties. In addition, DMF inhibits cell proliferation and significantly impairs xenograft tumor growth. Mechanistically, DMF prevents p65 nuclear translocation and attenuates its DNA binding activity but has no effect on upstream proteins in the NFB pathway. Dimethyl succinate, the inactive analog of DMF that lacks the electrophilic double bond of fumarate, is unable to inhibit NFB activity. Also, the cell-permeable thiol N-acetyl L-cysteine, reverses DMF inhibition of the NFB pathway, supporting the notion that the electrophile, DMF, acts via covalent modification. To determine whether DMF interacts directly with p65, we synthesized and used a novel chemical probe of DMF by incorporating an alkyne functionality and found that DMF covalently modifies p65, with cysteine 38 being essential for the activity of DMF. These results establish DMF as an NFB inhibitor with anti-tumor activity that may add therapeutic value in the treatment of aggressive breast cancers.In the United States, breast cancer is the second most prevalent cancer among women and claims over 40,000 lives each year. Despite major advancements in breast cancer treatment, a successful therapy outcome is limited to early detection of cancer at the primary organ. Therapy options for aggressive breast cancer disease (i.e. advanced stage, therapy-resistant, recurrent, or metastatic) are limited. As a result, the prognosis remains poor, and aggressive disease accounts for more than 90% of breast cancer-related deaths.Although the underlying mechanisms are not fully understood, inflammation has emerged as a key instigator and driver of aggressive breast cancers (1, 2). More specifically, the nuclear factor B (NFB) 2 pathway promotes multiple aggressive tumor phenotypes, including cell survival, migration, invasion, angiogenesis, and resistance to therapy (3, 4). The link between the inflammatory NFB pathway and breast cancer is also supported by the fact that a deregulated, or constitutively active, NFB pathway is associated with aggressive breast cancer phenotypes and therapy resistance (5-9). More recently, activation of the NFB pathway has been shown to regulate the survival and propagation of breast cancer stem cells (CSCs) (10 -12), which are a small subset of tumor cells that evade all standar...

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“…However, it remains to be established whether different breast cancer subtypes in BRCA1 mutation carriers respond equally to PARP inhibition. Reduced sensitivity of breast cancers to anticancer drugs has frequently been associated with an epithelial-to-mesenchymal transition (EMT) (4)(5)(6)(7). Metaplastic breast carcinomas (MBCs) are a subset of triple-negative breast cancers (TNBCs) characterized by a claudin-low and EMT-like phenotype (8) and a poor prognosis compared with other TNBCs (9).…”

mentioning

confidence: 99%

Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer

Henneman

Miltenburg

Michalak

et al. 2015

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

106

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Metaplastic breast carcinoma (MBC) is a rare histological breast cancer subtype characterized by mesenchymal elements and poor clinical outcome. A large fraction of MBCs harbor defects in breast cancer 1 (BRCA1). As BRCA1 deficiency sensitizes tumors to DNA cross-linking agents and poly(ADP-ribose) polymerase (PARP) inhibitors, we sought to investigate the response of BRCA1-deficient MBCs to the PARP inhibitor olaparib. To this end, we established a genetically engineered mouse model (GEMM) for BRCA1-deficient MBC by introducing the MET proto-oncogene into a BRCA1-associated breast cancer model, using our novel female GEMM ES cell (ESC) pipeline. In contrast to carcinomas, BRCA1-deficient mouse carcinosarcomas resembling MBC show intrinsic resistance to olaparib caused by increased P-glycoprotein (Pgp) drug efflux transporter expression. Indeed, resistance could be circumvented by using another PARP inhibitor, AZD2461, which is a poor Pgp substrate. These preclinical findings suggest that patients with BRCA1-associated MBC may show poor response to olaparib and illustrate the value of GEMM-ESC models of human cancer for evaluation of novel therapeutics. resistance | mouse model | breast cancer | BRCA1 | PARP P oly(ADP-ribose) polymerase (PARP) inhibition provides a promising therapeutic strategy for targeting homologous recombination (HR)-deficient tumors, such as breast cancer 1 (BRCA1)-mutated cancers (1). Indeed, clinical phase I and phase II trials have shown potent anticancer activity of small molecule inhibitors of PARP, such as olaparib, in patients with BRCA1-associated breast cancer (2, 3). However, it remains to be established whether different breast cancer subtypes in BRCA1 mutation carriers respond equally to PARP inhibition. Reduced sensitivity of breast cancers to anticancer drugs has frequently been associated with an epithelial-to-mesenchymal transition (EMT) (4-7). Metaplastic breast carcinomas (MBCs) are a subset of triple-negative breast cancers (TNBCs) characterized by a claudin-low and EMT-like phenotype (8) and a poor prognosis compared with other TNBCs (9). More than 60% of MBCs have BRCA1 promoter methylation, raising the question whether these tumors can be effectively targeted by using PARP inhibitors (10). To address this issue in an experimentally controlled setting, we set out to generate a genetically engineered mouse model (GEMM) of BRCA1-deficient MBC by inducing EMT via MET overexpression in a previously established GEMM of BRCA1-mutated breast cancer. We report that EMT is associated with olaparib resistance and can be effectively bypassed by administration of AZD2461, a PARP inhibitor with low affinity for the P-glycoprotein (Pgp) drug efflux transporter. Results Development of a GEMM-ESC Strategy for Mouse Mammary TumorModels. GEMMs have the potential to capture the cell-intrinsic and cell-extrinsic factors that drive de novo tumor formation, making them exceptionally valuable for cancer research (11). To speed up the development of novel multiallele GEMMs of human cancer, we...

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The Epithelial-to-Mesenchymal Transition and Cancer Stem Cells: A Coalition Against Cancer Therapies

Cited by 317 publications

References 131 publications

The BMP2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation

The BMP2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation

Dimethyl Fumarate Inhibits the Nuclear Factor κB Pathway in Breast Cancer Cells by Covalent Modification of p65 Protein

Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer

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