HMG‐CoA reductase expression in breast cancer is associated with a less aggressive phenotype and influenced by anthropometric factors

Borgquist, Signe; Djerbi, Soraya; Pontén, Fredrik; Anagnostaki, Lola; Goldman, M.; Gaber, Alexander; Manjer, Jonas; Landberg, Göran; Jirström, Karin

doi:10.1002/ijc.23597

Cited by 56 publications

(80 citation statements)

References 29 publications

(34 reference statements)

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“…In addition, we showed that f3-hydroxy-f3-methylglutaryl CoA reductase (HMG-CoA) reductase expression, a mevalonate pathway enzyme upstream of FPPS, was low in B02 cells as compared with that observed in T47D and MCF-7 cells (12). These results agree with an earlier report (18) (12,18, and this study), these results show that IPP/ApppI production in breast cancer cells depends on cellular uptake of N-BP and on mevalonate pathway activity associated with the ER status of the cell.…”

Section: N-bps Induced Human Vg9vd2 T-cell Expansion In Vitro and In supporting

confidence: 94%

In VivoPhosphoantigen Levels in Bisphosphonate-Treated Human Breast Tumors Trigger Vγ9Vδ2 T-cell Antitumor Cytotoxicity through ICAM-1 Engagement

Benzaïd

Mönkkönen

Bonnelye

et al. 2012

Clinical Cancer Research

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Purpose: Nitrogen-containing bisphosphonates (N-BP) such as zoledronate and risedronate exhibit antitumor effects. They block the activity of farnesyl pyrophosphate synthase (FPPS) in the mevalonate pathway, leading to intracellular accumulation of mevalonate metabolites (IPP/ApppI), which are recognized as tumor phosphoantigens by Vg9Vd2 T cells. However, mechanisms responsible for Vg9Vd2 T-cell recognition of N-BP-treated tumors producing IPP/ApppI remain unclear.Experimental Design: The effects of N-BPs on Vg9Vd2 T-cell expansion and anticancer activity were evaluated in vitro and in animal models of human breast cancers. The modalities of recognition of breast tumors by Vg9Vd2 T cells in N-BP-treated animals were also examined.Results: We found a strong correlation between Vg9Vd2 T-cell anticancer activity and intracellular accumulation of IPP/ApppI in risedronate-treated breast cancer cells in vitro. In addition, following risedronate treatment of immunodeficient mice bearing human breast tumors, human Vg9Vd2 T cells infiltrated and inhibited growth of tumors that produced high IPP/ApppI levels but not those expressing low IPP/ApppI levels. The combination of doxorubicin with a N-BP improved, however, Vg9Vd2 T-cell cytotoxicity against breast tumors expressing low IPP/ApppI levels. Moreover, Vg9Vd2 T-cell cytotoxicity in mice treated with risedronate or zoledronate did not only depend on IPP/ApppI accumulation in tumors but also on expression of tumor cell surface receptor intercellular adhesion molecule-1 (ICAM-1), which triggered the recognition of N-BP-treated breast cancer cells by Vg9Vd2 T cells in vivo.Conclusion: These findings suggest that N-BPs can have an adjuvant role in cancer therapy by activating Vg9Vd2 T-cell cytotoxicity in patients with breast cancer that produces high IPP/ApppI levels after N-BP treatment.

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Section: N-bps Induced Human Vg9vd2 T-cell Expansion In Vitro and In supporting

confidence: 94%

In VivoPhosphoantigen Levels in Bisphosphonate-Treated Human Breast Tumors Trigger Vγ9Vδ2 T-cell Antitumor Cytotoxicity through ICAM-1 Engagement

Benzaïd

Mönkkönen

Bonnelye

et al. 2012

Clinical Cancer Research

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“…2D). These results agree with data reported by Borgquist and colleagues (32) who showed that high HMG-CoA reductase expression correlated positively with ER expression in tumor tissue from patients with breast cancer. Altogether, these results show that IPP/ApppI production in breast cancer cells depends on cellular uptake of NBP and on the activity of the mevalonate pathway.…”

Section: Zol Induces Ipp/apppi Production In Human Breast Cancer Cellsupporting

confidence: 93%

High Phosphoantigen Levels in Bisphosphonate-Treated Human Breast Tumors Promote Vγ9Vδ2 T-Cell Chemotaxis and Cytotoxicity In Vivo

et al. 2011

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The nitrogen-containing bisphosphonate zoledronic acid (ZOL), a potent inhibitor of farnesyl pyrophosphate synthase, blocks the mevalonate pathway, leading to intracellular accumulation of isopentenyl pyrophosphate/ triphosphoric acid I-adenosin-5 0 -yl ester 3-(3-methylbut-3-enyl) ester (IPP/ApppI) mevalonate metabolites. IPP/ ApppI accumulation in ZOL-treated cancer cells may be recognized by Vg9Vd2 T cells as tumor phosphoantigens in vitro. However, the significance of these findings in vivo remains largely unknown. In this study, we investigated the correlation between the anticancer activities of Vg9Vd2 T cells and the intracellular IPP/ApppI levels in ZOL-treated breast cancer cells in vitro and in vivo. We found marked differences in IPP/ApppI production among different human breast cancer cell lines post-ZOL treatment. Coculture with purified human Vg9Vd2 T cells led to IPP/ApppI-dependent near-complete killing of ZOL-treated breast cancer cells. In ZOLtreated mice bearing subcutaneous breast cancer xenografts, Vg9Vd2 T cells infiltrated and inhibited growth of tumors that produced high IPP/ApppI levels, but not those expressing low IPP/ApppI levels. Moreover, IPP/ ApppI not only accumulated in cancer cells but it was also secreted, promoting Vg9Vd2 T-cell chemotaxis to the tumor. Without Vg9Vd2 T-cell expansion, ZOL did not inhibit tumor growth. These findings suggest that cancers-producing high IPP/ApppI levels after ZOL treatment are most likely to benefit from Vg9Vd2 T-cellmediated immunotherapy. Cancer Res; 71(13); 4562-72. Ó2011 AACR.

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“…As our work was in progress, three tissue microarray studies reported that higher expression of HMGCR correlates with favorable breast and ovarian cancer patient prognosis (38)(39)(40). However, the antibody used in their studies is one that we showed is unable to detect human HMGCR (Fig.…”

Section: Discussionmentioning

confidence: 89%

Dysregulation of the mevalonate pathway promotes transformation

Clendening

Pandyra

Boutros

et al. 2010

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

343

306

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The importance of cancer metabolism has been appreciated for many years, but the intricacies of how metabolic pathways interconnect with oncogenic signaling are not fully understood. With a clear understanding of how metabolism contributes to tumorigenesis, we will be better able to integrate the targeting of these fundamental biochemical pathways into patient care. The mevalonate (MVA) pathway, paced by its rate-limiting enzyme, hydroxymethylglutaryl coenzyme A reductase (HMGCR), is required for the generation of several fundamental end-products including cholesterol and isoprenoids. Despite years of extensive research from the perspective of cardiovascular disease, the contribution of a dysregulated MVA pathway to human cancer remains largely unexplored. We address this issue directly by showing that dysregulation of the MVA pathway, achieved by ectopic expression of either full-length HMGCR or its novel splice variant, promotes transformation. Ectopic HMGCR accentuates growth of transformed and nontransformed cells under anchorage-independent conditions or as xenografts in immunocompromised mice and, importantly, cooperates with RAS to drive the transformation of primary mouse embryonic fibroblasts cells. We further explore whether the MVA pathway may play a role in the etiology of human cancers and show that high mRNA levels of HMGCR and additional MVA pathway genes correlate with poor prognosis in a meta-analysis of six microarray datasets of primary breast cancer. Taken together, our results suggest that HMGCR is a candidate metabolic oncogene and provide a molecular rationale for further exploring the statin family of HMGCR inhibitors as anticancer agents.HMGCR | hydroxymethylglutaryl coenzyme A reductase | cancer | metabolic oncogene | tumor metabolism

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HMG‐CoA reductase expression in breast cancer is associated with a less aggressive phenotype and influenced by anthropometric factors

Cited by 56 publications

References 29 publications

In VivoPhosphoantigen Levels in Bisphosphonate-Treated Human Breast Tumors Trigger Vγ9Vδ2 T-cell Antitumor Cytotoxicity through ICAM-1 Engagement

In VivoPhosphoantigen Levels in Bisphosphonate-Treated Human Breast Tumors Trigger Vγ9Vδ2 T-cell Antitumor Cytotoxicity through ICAM-1 Engagement

High Phosphoantigen Levels in Bisphosphonate-Treated Human Breast Tumors Promote Vγ9Vδ2 T-Cell Chemotaxis and Cytotoxicity In Vivo

Dysregulation of the mevalonate pathway promotes transformation

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