Increased Cholesterol Biosynthesis Is a Key Characteristic of Breast Cancer Stem Cells Influencing Patient Outcome

Publication date: 25 June 2019Source: Cell Reports, Volume 27, Issue 13Author(s): Sidse Ehmsen, Martin H. Pedersen, Guisong Wang, Mikkel G. Terp, Amina Arslanagic, Brian L. Hood, Thomas P. Conrads, Rikke Leth-Larsen, Henrik J. DitzelSummaryTumor eradication may be greatly improved by targeting cancer stem cells (CSCs), as they exhibit resistance to conventional therapy. To gain insight into the unique biology of CSCs, we developed patient-derived xenograft tumors (PDXs) from ER− breast cancers from which we isolated mammospheres that are enriched for CSCs. Comparative global proteomic analysis was performed on patient tumor tissues and corresponding PDXs and mammospheres. Mammospheres exhibited increased expression of proteins associated with de novo cholesterol synthesis. The clinical relevance of increased cholesterol biosynthesis was verified in a large breast cancer cohort showing correlation with shorter relapse-free survival. RNAi and chemical inhibition of the cholesterol biosynthesis pathway reduced mammosphere formation, which could be rescued by a downstream metabolite. Our findings identify the cholesterol biosynthesis pathway as central for CSC propagation and a potential therapeutic target, as well as providing a mechanistic explanation for the therapeutic benefit of statins in breast cancer.Graphical Abstract
Source: Cell Reports - Category: Cytology Source Type: research

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The mevalonate pathway (also known as the cholesterol biosynthesis pathway) plays a crucial metabolic role in normal cell function as well as in the pathological environment. It leads to the synthesis of sterol and non-sterol isoprenoid biomolecules which subserve a variety of cellular functions. It is known to be deregulated in many disease processes. Statins and bisphosphonates are prominent inhibitors of the mevalonate pathway. They inhibit cell proliferation and activate apoptotic signalling and suppress tumour growth. Statins subdue metastatic spread of tumours by virtue of their ability to suppress invasion and angio...
Source: Current Cancer Therapy Reviews - Category: Cancer & Oncology Source Type: research
Ryan R. Kelly1,2†, Lindsay T. McDonald1,2†, Nathaniel R. Jensen1,2, Sara J. Sidles1,2 and Amanda C. LaRue1,2* 1Research Services, Ralph H. Johnson VA Medical Center, Charleston, SC, United States 2Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, United States The significant biochemical and physiological effects of psychological stress are beginning to be recognized as exacerbating common diseases, including osteoporosis. This review discusses the current evidence for psychological stress-associated mental health disorders as risk factors for os...
Source: Frontiers in Psychiatry - Category: Psychiatry Source Type: research
Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more. This content is...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
This article, however, is more of a commentary on high level strategy and the effects of regulation, coupled with a desire to forge ahead rather than hold back in the matter of treating aging, thus I concur with much more of what is said than is usually the case. For decades, one of the most debated questions in gerontology was whether aging is a disease or the norm. At present, excellent reasoning suggests aging should be defined as a disease - indeed, aging has been referred to as "normal disease." Aging is the sum of all age-related diseases and this sum is the best biomarker of aging. Aging and its d...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
Publication date: Available online 4 April 2018Source: Biochimica et Biophysica Acta (BBA) - BioenergeticsAuthor(s): Marco Fiorillo, Maria Peiris-Pagès, Rosa Sanchez-Alvarez, Lucia Bartella, Leonardo Di Donna, Vincenza Dolce, Giovanni Sindona, Federica Sotgia, Anna Rita Cappello, Michael P. LisantiAbstractHere, we show that a 2:1 mixture of Brutieridin and Melitidin, termed “BMF”, has a statin-like properties, which blocks the action of the rate-limiting enzyme for mevalonate biosynthesis, namely HMGR (3-hydroxy-3-methylglutaryl-CoA-reductase). Moreover, our results indicate that BMF functionally inhibit...
Source: Biochimica et Biophysica Acta (BBA) Bioenergetics - Category: Biochemistry Source Type: research
ti MP Abstract Here, we show that a 2:1 mixture of Brutieridin and Melitidin, termed "BMF", has a statin-like properties, which blocks the action of the rate-limiting enzyme for mevalonate biosynthesis, namely HMGR (3-hydroxy-3-methylglutaryl-CoA-reductase). Moreover, our results indicate that BMF functionally inhibits several key characteristics of CSCs. More specifically, BMF effectively i) reduced ALDH activity, ii) blocked mammosphere formation and iii) inhibited the activation of CSC-associated signalling pathways (STAT1/3, Notch and Wnt/beta-catenin) targeting Rho-GDI-signalling. In addition, BMF m...
Source: Biochimica et Biophysica Acta - Category: Biochemistry Authors: Tags: Biochim Biophys Acta Source Type: research
If your doctor puts you on a statin for cholesterol, prepare to be on it for life. If you have high blood pressure, you can be sure you'll be filling that prescription forever. Diabetic? You can look forward to decades of metformin. Big Pharma seems to have a "treatment" for every disease. But they rarely have a "cure." You see, the longer you take their "medicine," the more money they make. And now they're trying to do the same thing with chemotherapy drugs. A group of researchers from Oregon and the U.K. just created a new drug delivery system for cancer. It's called "m...
Source: Al Sears, MD Natural Remedies - Category: Complementary Medicine Authors: Tags: Cancer Source Type: news
This study teaches us that poor wound healing and wrinkling and sagging that occur in aging skin share similar mechanisms." Reduced cell cohesiveness of outgrowths from eccrine sweat glands delays wound closure in elderly skin Human skin heals more slowly in aged vs. young adults, but the mechanism for this delay is unclear. In humans, eccrine sweat glands (ESGs) and hair follicles underlying wounds generate cohesive keratinocyte outgrowths that expand to form the new epidermis. Our results confirm that the outgrowth of cells from ESGs is a major feature of repair in young skin. Strikingly, in aged s...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
Conclusions: Metformin regulates cancer cells by multiple pathways including reduction in cell growth, increases in apoptosis and alterations in cellular metabolism. The effects on the cholesterol pathway are both extensive and affect multiple downstream pathways including EGFR, Akt, and MAPK. Partial funding was provided by the Susan G. Komen Foundation. Citation Format: Ann D Thor, Zeying Fan, Reema Wahdan-Alaswad, Steve M Anderson, Jennifer K Richer, Susan M Edgerton. Metformin blocks de novo synthesis of cholesterol in triple negative breast cancer cells [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AAC...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Poster Session Abstracts Source Type: research
As we move towards the end of the year, like all news sources, we fall back on that classic space filler – the list story. So without further ado, here is the official Behind the Headlines Top Five of Top Fives stories of 2014, in which we celebrate the good, highlight the bad, check out the weird and answer some of the burning questions of the year. The top five 'Good work boffins!' stories of the year We can often get bogged down in pointing out dodgy sub-group analyses, spurious extrapolations of sample sizes containing just 20 rats and a water maze, and RCTs pointing out the benefits of cherries on dementia preve...
Source: NHS News Feed - Category: Consumer Health News Tags: QA articles Medical practice Source Type: news
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