Therapeutic Potential of Matrix Metalloproteinase Inhibition in Breast Cancer

Radisky, Evette S.; Raeeszadeh‐Sarmazdeh, Maryam; Radisky, Derek C.

doi:10.1002/jcb.26185

Cited by 107 publications

(97 citation statements)

References 239 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…As discussed earlier, we and others have identified astrocyte secreted MMP-2, MMP-9, and MMP-1 to promote tumor progression, and blocking them with broad spectrum MMP inhibitors does influence tumor metastasis in pre-clinical models [95,96,[165][166][167]. Interestingly, MMP-1 was one of 21 MMPs that showed clinical significance in regards to breast cancer brain metastasis, and expression analysis of brain-seeking triple negative breast cancer clonal cells confirm MMP-1 and MMP-9 as potential targets [133,168].…”

Section: Enzyme Targetsmentioning

confidence: 64%

The Role of Astrocytes in Tumor Growth and Progression

Gronseth¹,

Wang²,

Harder³

et al. 2018

Astrocyte - Physiology and Pathology

View full text Add to dashboard Cite

Current research is continually implicating the importance of astrocytes as active participants in neurological injury, disease, and tumor progression. This chapter will discuss some of these emerging concepts, especially as they relate to tumor biology. Astrocytes themselves can become tumorigenic, such as the case in gliomas, which often have aberrant signaling in key regulating genes of astrocyte development. Astrocytes secrete factors that maintain the tight junctions of the blood brain barrier (BBB), which in turn regulates the success or failure of metastatic cells extravasating into the brain. This astrocytic association with the brain vasculature also promotes brain tumor stem cell characteristics, which are known to be necessary for tumor initiation. Tumor cells within the brain make direct contacts with astrocytes through gap junctions, which subsequently lead to increased chemoresistance of the tumor cells. Astrocytes have also been shown to effect tumors cells via secretion of degradative enzymes, cytokines, chemokines, and growth factors, all of which have been shown to promote tumor cell proliferation, survival, and invasion. Thus, research in astrocyte biology and the role of astrocytes in the tumor microenvironment has and will likely continue to reveal novel targets for cancer intervention.

show abstract

Section: Enzyme Targetsmentioning

confidence: 64%

The Role of Astrocytes in Tumor Growth and Progression

Gronseth¹,

Wang²,

Harder³

et al. 2018

Astrocyte - Physiology and Pathology

View full text Add to dashboard Cite

show abstract

“…In this case, the reduction of β‐catenin could be the primary effect. MMPs are known to be regulated at multiple levels, including proteolysis of precursor proteins (pro‐MMPs) and regulation of activity through tissue inhibitors of metalloproteinases [reviewed in (39)]. Therefore, elevated MMP mRNA levels could alternatively be a compensatory mechanism for reduced pro‐MMP cleavage or MMP activity.…”

Section: Discussionmentioning

confidence: 99%

Hexose‐6‐phosphate dehydrogenase controls cancer cell proliferation and migration through pleiotropic effects on the unfolded‐protein response, calcium homeostasis, and redox balance

et al. 2018

View full text Add to dashboard Cite

Hexose-6-phosphate dehydrogenase (H6PD) produces reduced NADPH in the endoplasmic reticulum (ER) lumen. NADPH constitutes a cofactor for many reducing enzymes, and its inability to traverse biologic membranes makes in situ synthesis of NADPH in the ER lumen indispensable. The H6PD gene is amplified in several types of malignancies, and earlier work pointed toward a potential involvement of the enzyme in cancer cell growth. In the present study, we demonstrated a pivotal role of H6PD in proliferation and migratory potential of 3 human breast cancer cell lines. Knockdown of H6PD decreased proliferation and migration in SUM159, MCF7, and MDA-MB-453 cells. To understand the mechanism through which H6PD exerts its effects, we investigated the cellular changes after H6PD silencing in SUM159 cells. Knockdown of H6PD resulted in an increase in ER lumen oxidation, and down-regulation of many components of the unfolded protein response, including the transcription factors activating transcription factor-4, activating transcription factor-6, split X-box binding protein-1, and CCAAT/enhancer binding protein homologous protein. This effect was accompanied by an increase in sarco/endoplasmic reticulum Ca2+-ATPase-2 pump expression and an decrease in inositol trisphosphate receptor-III, which led to augmented levels of calcium in the ER. Further characterization of the molecular pathways involving H6PD could greatly broaden our understanding of how the ER microenvironment sustains malignant cell growth.—Tsachaki, M., Mladenovic, N., Štambergová, H., Birk, J., Odermatt, A. Hexose-6-phosphate dehydrogenase controls cancer cell proliferation and migration through pleiotropic effects on the unfolded protein response, calcium homeostasis, and redox balance.

show abstract

“…Designing inhibitors that act against a single or narrow range of MMPs is clearly important for targeting MMPs in diseases and much effort in this direction has been recently reported [52]. In this work, we attempted to engineer such an inhibitor starting from the natural broad MMP inhibitor, N-TIMP2.…”

Section: Discussionmentioning

confidence: 99%

Converting a broad matrix metalloproteinase family inhibitor into a specific inhibitor of MMP-9 and MMP-14

Shirian

Arkadash

Cohen

et al. 2017

Preprint

Self Cite

View full text Add to dashboard Cite

MMP-14 and MMP-9 are two well established cancer targets for which no specific clinically relevant inhibitor is available. Using a powerful combination of computational design and yeast surface display technology, we engineered such an inhibitor starting from a non-specific MMP inhibitor, N-TIMP2. The engineered purified N-TIMP2 variants showed enhanced specificity towards MMP-14 and MMP-9 relative to a panel of off-target MMPs. MMP-specific N-TIMP2 sequence signatures were obtained that could be understood from the structural perspective of MMP/N-TIMP2 interactions. Our MMP-9 inhibitor exhibited 1000-fold preference for MMP-9 vs. MMP-14, which is likely to translate into significant differences under physiological conditions. Our results provide new insights regarding evolution of promiscuous proteins and optimization strategies for design of inhibitors with single-target specificities.

show abstract

Therapeutic Potential of Matrix Metalloproteinase Inhibition in Breast Cancer

Cited by 107 publications

References 239 publications

The Role of Astrocytes in Tumor Growth and Progression

The Role of Astrocytes in Tumor Growth and Progression

Hexose‐6‐phosphate dehydrogenase controls cancer cell proliferation and migration through pleiotropic effects on the unfolded‐protein response, calcium homeostasis, and redox balance

Converting a broad matrix metalloproteinase family inhibitor into a specific inhibitor of MMP-9 and MMP-14

Contact Info

Product

Resources

About