Kulvinder ¹, Gautam N², Gautam NK Allahbadia² and Mandeep Singh³

¹Obstetrics and Gynaecology, Specialist Reproductive Endocrinology and Infertility Specialist, Scientific Director Dr Kulvinder Kochar Kaur, Dr Kulvinder Kaur Centre for Human Reproduction, Jalandhar, Punjab, India
²Obstetrics and Gynaecology, D.N.B, Scientific Director, Ex-Rotunda-A Centre for Human Reproduction, Mumbai, India
³Consultant Neurologist, Swami Satyanand Hospital Near Nawi Kachehri, Baradri, Punjab, India

*Corresponding Author: Kulvinder, Obstetrics and Gynaecology, Specialist Reproductive Endocrinology and Infertility Specialist, Scientific Director Dr Kulvinder Kochar Kaur, Dr Kulvinder Kaur Centre for Human Reproduction, Jalandhar, Punjab, India.

Received: November 22, 2022; Published: February 24, 2023

Abstract

Breast Cancer (BC) represents one of the commonest cancer in case of women. During 2018 it was calculated that mortality of 627, 800 women occurred due to BC. BC has multiple factors contributing to its etiology besides is a chronic disease. Earlier we updated the pathophysiology and treatment of BC. Despite significant advancements have been made regarding its treatment, numerous queries remain regarding carcinogenesis. At the time of carcinogenesis cells illustrate decontrolled cholesterol homeostasis. Subsequent to this intracellular cholesterol accrual takes place which is the requirement for sustenance of greater growth rate. Both cholesterol efflux along with influx represent 2 metabolic pathways which is essential for avoidance of intracellular cholesterol accrual. Liver X receptor (LXRs) reflect nuclear receptors which following activation result in the expression of ABC transporters implicated in facilitating cholesterol efflux besides causing Induction of IDOL (inducible degrader of low density lipoprotein receptor (LDLR) implicated in cholesterol influx reduction. Oxysterols are oxygenated cholesterol products that get generated via various pathways have been invented in the form of LXR particular ligands. Certain Oxysterols are implicated in tumor generation, whereas others are believed to work as anti tumor substances. Thus here we conducted a narrative review utilizing search engine pubmed, google scholar; web of science; embase; Cochrane review library utilizing the MeSH terms like Breast Cancer; cholesterol homeostasis; LXRs; Oxysterols; 27OHC; pro-protein convertase subtilisn/kexin type9 (PCSK9) in BC generation, from 1983 till date 2022. We found over 2000 articles where we used 50 articles due to journal specification for this review. Here we detail regarding the implication of cholesterol, Oxysterols along with LXRs in the pathophysiology of BC, highlighting the biological actions of LXRs ligands. Further the part of PCSK9 regarding the breast cancer robustness along with cholesterogenic gene signatures might aid in anticipating prognosis of young breast cancer patients.

Keywords: BC; Cholesterol; LXRs; Oxysterols

References

1. Must A., et al. “The disease burden associated with overweight and obesity”. JAMA 282 (1999): 1523-1529.
2. Law MR and Thompson SG. “Low serum cholesterol and the risk of Cancer: an analysis of the published prospective studies”. Cancer Causes Control 2 (1991): 253-261.
3. Garcia-Estevez L and Moreno-BuenoG. “Updating the role of obesity and cholesterol in Breast Cancer”. Breast Cancer Research1 (2019): 35.
4. ElRoz A., et al. “LXR agonists and ABCG dependent cholesterol efflux in MCF-7 Breast Cancer cells: reaction to proliferation and apoptosis”. Anticancer Research 32 (2012): 3007-3013.
5. Carbonnelle D., et al. “LXR activation downregulates lipid rafts markers FLOT2 and DHHC5 efflux in MCF-7 Breast Cancer cells”. Anticancer Research 37 (2017): 4067-4073.
6. Fukuchi J., et al. “Antiproliferative effect of Liver X receptor agonists on LNCaP human prostate Cancer cells”. Cancer Research 64 (2004): 7686-7689.
7. Chuu CP and Lin HP. “Antiproliferative effect of LXR agonists T0901317 and 22 (R) hydroxy cholesterol (22 (R)-OHC) on multiple human Cancer cell lines”. Anticancer Research 30 (2010): 3643-3648.
8. Kulvinder Kochar Kaur., et al. “Novel ways of targeting triple negative breast cancer (TNBC) with the latest research-Will it improve prognoses”. Journal of Gynaecology (2019).
9. Kulvinder Kochar Kaur., et al. “An update on the Screening, diagnosis and Management of Breast Cancer –A Review with considerations for future fertility” (2021).
10. Nazih H and Bard JM. “Cholesterol, oxysterols, and LXRs in Breast Cancer pathophysiology”. International Journal of Molecular Sciences 21 (2020): 1356.
11. Wei W., et al. “Ligand activation of ERR alpha by cholesterol mediates statin and bisphosphonate effects”. Cell Metabolism 23 (2016): 479-491.
12. Llaverias G., et al. “Role of cholesterol in the development and progression of Breast Cancer”. American Journal of Pathology 178 (2011): 402-412.
13. Hoque M., et al. “The crosstalk of LDL cholesterol with cell motility: insights from Niemann Pick type C1mutation and altered integrin trafficking”. Cell Adhesion and Migration 9 (2015): 384-391.
14. Antalis CJ., et al. “Migration of MDA-MB-231 Breast Cancer cells depends on the availability of exogenous lipids and cholesterol esterification”. Breast Cancer Research and Treatment 28 (2011): 733-741.
15. , et al. “The role of cholesterol metabolism and cholesterol transport in carcinogenesis :a review of scientific findings relevant to future Cancer therapeutics”. Frontiers in Pharmacology 4 (2013): 119.
16. Danilo C., et al. “Scavenger receptor class B type 1 regulates cellular cholesterol metabolism and cell signaling associated with breast cancer development”. Breast Cancer Research 15 (2013): 87.
17. Kryer JR and Phan L. “A key cells regulator of cholesterol homeostasis, SREBP2, can be targeted in prostate Cancer with natural products”. Biochemistry Journal 446 (2012): 191-201.
18. Shibata MA., et al. “Comparative effects of lovastatin on mammary and prostate oncogenesis in transgenic mouse models”. Carcinogenesis 243 (2003): 453-459.
19. Bai F., et al. “Simvastatin induces breast cancer cell death through Oxidative stress upregulating miR-140-5p”. Aging 11 (2019): 3198-3219.
20. Clayman RV., et al. “Cholesterol accumulation in hetero transplanted renal cancer cells”. Journal of Urology 129 (1983): 621-624.
21. Zelcer N., et al. “LXR regulates cholesterol uptake through Idol dependent ubiquitination of the LDL receptor”. Science 325 (2009): 100-104.
22. dos Santos CR., et al. “LDL-cholesterol signaling induces breast cancer proliferation and invasion”. Lipids Health Disease 13 (2014): 16.
23. Jaworsky K., et al. “PCSK9 inhibitors-from discovery of a single mutation to a ground breaking therapy of lipid disorders in one decade”. Archives of Medical Science 13 (2017): 914-929.
24. Momtazi-Borojeni AA., et al. “Effects of immunization against PCSK9 in an experimental model of breast cancer”. Archives of Medical Science 15 (2019): 570-579.
25. Chang SJ., et al. “The association between lipid profiles and breast cancer among Taiwanese women”. Clinical Chemistry and Laboratory Medicine 45 (2007): 1219-1223.
26. Kim Y., et al. “Serum high density lipoprotein cholesterol and breast cancer risk by menopausal status, body mass index and hormonal receptor in Korea”. Cancer Epidemiology, Biomarkers and Prevention 18 (2009): 508-515.
27. Kuchanska-Newton AM., et al. “HDL-cholesterol and incidence of breast cancer in the ARIC cohort study”. Annals of Epidemiology 18 (2008): 671-677.
28. Potluri R., et al. “P740 hyperlipidemia as a risk factor for breast cancer?” Cardiovascular Research 103 (2014): S135.
29. Laisupasin P., et al. “Comparison of serum lipid profiles between normal controls and breast cancer patients”. Journal of Lab Physicians 5 (2013): 38-41.
30. Touvier M., et al. “Cholesterol and breast cancer risk: a systematic review and meta-analysis of prospective studies”. British Journal of Nutrition 114 (2015): 347-57.
31. Carter PR., et al. “Hyperlipidemia reduces mortality in breast, prostate, lung and bowel Cancer”. Heart 102 (2016): A57-A58.
32. , et al. “Canadian Cancer registries Epidemiology researchers G: dietary cholesterol intake and breast cancer”. Annals of Oncology 23 (2012): 491-500.
33. , et al. “Systematic review and meta-analysis suggests that dietary cholesterol increases risk of breast cancer”. Nutrition Research 36 (2016): 627-635.
34. , et al. “Exploring association between statin use and breast cancer risk: an updated meta-analysis”. Archives of Gynecology and Obstetrics 296 (2017): 1043-1053.
35. Mansourian M., et al. “Statin use and risk recurrence and death: a systematic review and meta-analysis of observational studies”. Journal of Pharmaceutical Sciences 19 (2016): 72-81.
36. Bovenga F., et al. “Uncoupling nuclear receptor LXR and cholesterol metabolism in cancer”. Cell Metabolism 21 (2015): 517-526.
37. Nelson ER. “The significance of cholesterol and its metabolite 27-hydroxy cholesterol in breast cancer”. Molecular and Cellular Endocrinology 466 (2018): 73-80.
38. Nelson ER., et al. “The oxysterol 27-hydroxy cholesterol, links cholesterol metabolism to bone homeostasis through its actions on the estrogen and Liver X receptors”. Endocrinology 152 (2011): 4691-705.
39. Wu Q., et al. “27-hydroxy cholesterol promotes cell autonomous ER positive breast cancer growth”. Cell Report 5 (2013): 637-645.
40. , et al. “Fast liquid chromatography- mass spectrometry revealed side chain oxysterols heterogeneity”. The Journal of Steroid Biochemistry and Molecular Biology 192 (2019): 105309.
41. Roberg-LarsenH., et al. “Mass spectrometric detection of 27- hydroxy cholesterol in breast cancer steroid hormone exosomes”. The Journal of Steroid Biochemistry and Molecular Biology 169 (2017): 22-28.
42. , et al. “Circulating 27-hydroxy cholesterol and breast cancer risk : results from the EPIC Heidelberg cohort”. Journal of the National Cancer Institute 111 (2019): 365-371.
43. Dalenc F., et al. “Circulating oxysterol metabolites as potential new surrogate markers in patients with hormone receptor positive breast cancer : results of the OXYSTAM”. The Journal of Steroid Biochemistry and Molecular Biology 169 (2016): 210-218.
44. Hutchison SA., et al. “ER negative breast cancer is highly responsive to cholesterol metabolite signaling”. Nutrients 11 (2019): 2618.
45. Jalaguier S., et al. “Complex regulation of LCoR signaling in breast cancer cells”. Oncogene 36 (2017): 4790-4801.
46. , et al. “Expression of LXR β, ABCA1, and ABCG1 in human triple negative breast cancer tissues”. Oncology Report 42 (2019): 1869-1877.
47. Gomig THB., et al. “Quantitative label free mass spectrometry using contralateral and adjacent breast tissues reveal differentially expressed proteins and their predicted impacts on pathways and cellular functions in breast cancer”. Journal of Proteomics 199 (2019): 1-14.
48. Torres-Luquis O., et al. “LXR/RXR pathway signaling associated with triple negative breast cancer in African American women”. Breast Cancer 11 (2019): 1-12.
49. Chong EW., et al. “Circulating levels of PCSK9, ANGPTL3 and Lp (a) in Stage III breast cancers”. BMJ Cancer1 (2022): 1049.
50. Li X., et al. “A cholesterologenic gene signature for predicting the prognosis of young breast cancer patients”. Peer Journal 10 (2022): e13922.

Citation

Citation: Kulvinder.,et al. “Dysregulated Cholesterol Metabolism Including Oxysterols in the Pathophysiology of Breast Cancer: Therapeutic Implications - A Narrative Review" Acta Scientific Cancer Biology 7.1 (2023): 07-14.

Copyright

Copyright: © 2022 Kulvinder.,et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.