The angiotensin receptor blocker, Losartan, inhibits mammary tumor development and progression to invasive carcinoma
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Coulson, Rhiannon; Liew, Seng; Connelly, Angela; Yee, Nicholas; Deb, Siddhartha; Kumar, Beena; Vargas, Ana; O'Toole, Sandra; Parslow, Adam; Poh, Ashleigh; Putoczki, Tracy; Morrow, Riley; Alorro, Mariah; Lazarus, Kyren; Yeap, Evie; Walton, Kelly; Harrison, Craig; Hannan, Natalie; George, Amee; Clyne, Colin; Ernst, Matthias; Allen, Andrew; Chand, Ashwini
Description
Drugs that target the Renin-Angiotensin System (RAS) have recently come into focus for their potential utility as cancer treatments. The use of Angiotensin Receptor Blockers (ARBs) and Angiotensin-Converting Enzyme (ACE) Inhibitors (ACEIs) to manage hypertension in cancer patients is correlated with improved survival outcomes for renal, prostate, breast and small cell lung cancer. Previous studies demonstrate that the Angiotensin Receptor Type I (AT1R) is linked to breast cancer pathogenesis,...[Show more]
dc.contributor.author | Coulson, Rhiannon | |
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dc.contributor.author | Liew, Seng | |
dc.contributor.author | Connelly, Angela | |
dc.contributor.author | Yee, Nicholas | |
dc.contributor.author | Deb, Siddhartha | |
dc.contributor.author | Kumar, Beena | |
dc.contributor.author | Vargas, Ana | |
dc.contributor.author | O'Toole, Sandra | |
dc.contributor.author | Parslow, Adam | |
dc.contributor.author | Poh, Ashleigh | |
dc.contributor.author | Putoczki, Tracy | |
dc.contributor.author | Morrow, Riley | |
dc.contributor.author | Alorro, Mariah | |
dc.contributor.author | Lazarus, Kyren | |
dc.contributor.author | Yeap, Evie | |
dc.contributor.author | Walton, Kelly | |
dc.contributor.author | Harrison, Craig | |
dc.contributor.author | Hannan, Natalie | |
dc.contributor.author | George, Amee | |
dc.contributor.author | Clyne, Colin | |
dc.contributor.author | Ernst, Matthias | |
dc.contributor.author | Allen, Andrew | |
dc.contributor.author | Chand, Ashwini | |
dc.date.accessioned | 2021-09-23T04:07:34Z | |
dc.date.available | 2021-09-23T04:07:34Z | |
dc.identifier.issn | 1949-2553 | |
dc.identifier.uri | http://hdl.handle.net/1885/248706 | |
dc.description.abstract | Drugs that target the Renin-Angiotensin System (RAS) have recently come into focus for their potential utility as cancer treatments. The use of Angiotensin Receptor Blockers (ARBs) and Angiotensin-Converting Enzyme (ACE) Inhibitors (ACEIs) to manage hypertension in cancer patients is correlated with improved survival outcomes for renal, prostate, breast and small cell lung cancer. Previous studies demonstrate that the Angiotensin Receptor Type I (AT1R) is linked to breast cancer pathogenesis, with unbiased analysis of gene-expression studies identifying significant up-regulation of AGTR1, the gene encoding AT1R in ER+ve/HER2-ve tumors correlating with poor prognosis. However, there is no evidence, so far, of the functional contribution of AT1R to breast tumorigenesis. We explored the potential therapeutic benefit of ARB in a carcinogen-induced mouse model of breast cancer and clarified the mechanisms associated with its success.Mammary tumors were induced with 7,12-dimethylbenz[α]antracene (DMBA) and medroxyprogesterone acetate (MPA) in female wild type mice and the effects of the ARB, Losartan treatment assessed in a preventative setting (n = 15 per group). Tumor histopathology was characterised by immunohistochemistry, real-time qPCR to detect gene expression signatures, and tumor cytokine levels measured with quantitative bioplex assays. AT1R was detected with radiolabelled ligand binding assays in fresh frozen tumor samples.We showed that therapeutic inhibition of AT1R, with Losartan, resulted in a significant reduction in tumor burden; and no mammary tumor incidence in 20% of animals. We observed a significant reduction in tumor progression from DCIS to invasive cancer with Losartan treatment. This was associated with reduced tumor cell proliferation and a significant reduction in IL-6, pSTAT3 and TNFα levels. Analysis of tumor immune cell infiltrates, however, demonstrated no significant differences in the recruitment of lymphocytes or tumour-associated macrophages in Losartan or vehicle-treated mammary tumors.Analysis of AT1R expression with radiolabelled ligand binding assays in human breast cancer biopsies showed high AT1R levels in 30% of invasive ductal carcinomas analysed. Furthermore, analysis of the TCGA database identified that high AT1R expression to be associated with luminal breast cancer subtype.Our in vivo data and analysis of human invasive ductal carcinoma samples identify the AT1R is a potential therapeutic target in breast cancer, with the availability of a range of well-tolerated inhibitors currently used in clinics. We describe a novel signalling pathway critical in breast tumorigenesis, that may provide new therapeutic avenues to complement current treatments. | |
dc.description.sponsorship | This research was supported by grants from the National Breast Cancer Foundation and the CASS Foundation (ALC). We acknowledge the support of Victorian Government’s Operational Infrastructure Support Program and the National Health and Medical Research Council (NHMRC) of Australia Grants. ALC is supported by an NHMRC Career Development Fellowship (ID 1062247). We also acknowledge funding from the Sydney Breast Cancer Foundation (S.A.O’T), the RT Hall Foundation (S.A.O’T), Tag Family Foundation (S.A.O’T), and the O’Sullivan family (S.A.O’T). | |
dc.format.mimetype | application/pdf | |
dc.language.iso | en_AU | |
dc.publisher | Impact Journals | |
dc.source | Oncotarget | |
dc.title | The angiotensin receptor blocker, Losartan, inhibits mammary tumor development and progression to invasive carcinoma | |
dc.type | Journal article | |
local.description.notes | Imported from ARIES | |
local.identifier.citationvolume | 8 | |
dc.date.issued | 2017 | |
local.identifier.absfor | 111204 - Cancer Therapy (excl. Chemotherapy and Radiation Therapy) | |
local.identifier.absfor | 111201 - Cancer Cell Biology | |
local.identifier.absfor | 111207 - Molecular Targets | |
local.identifier.ariespublication | u1042365xPUB9 | |
local.publisher.url | http://www.impactjournals.com/ | |
local.type.status | Published Version | |
local.contributor.affiliation | Coulson, Rhiannon, Hudson's Institute of Medical Research | |
local.contributor.affiliation | Liew, Seng, Monash University | |
local.contributor.affiliation | Connelly, Angela, University of Melbourne | |
local.contributor.affiliation | Yee, Nicholas, Olivia Newtoon-John Cancer Research Institute | |
local.contributor.affiliation | Deb, Siddhartha, Olivia Newton-John Cancer Research Institute | |
local.contributor.affiliation | Kumar, Beena, Monash Health | |
local.contributor.affiliation | Vargas, Ana, Royal Prince Alfred Hospital | |
local.contributor.affiliation | O'Toole, Sandra, Royal Prince Alfred Hospital | |
local.contributor.affiliation | Parslow, Adam, Olivia Newton-John Cancer Research Institute | |
local.contributor.affiliation | Poh, Ashleigh, Walter & Eliza Hall Institute of Medical Research | |
local.contributor.affiliation | Putoczki, Tracy, Walter & Eliza Hall Institute of Medical Research | |
local.contributor.affiliation | Morrow, Riley, Olivia Newton-John Cancer Research Institute | |
local.contributor.affiliation | Alorro, Mariah, Olivia Newton-John Cancer Research Institute | |
local.contributor.affiliation | Lazarus, Kyren, Hudson's Institute of Medical Research | |
local.contributor.affiliation | Yeap, Evie, Hudson's Institute of Medical Research | |
local.contributor.affiliation | Walton, Kelly, Monash University | |
local.contributor.affiliation | Harrison, Craig, Monash University | |
local.contributor.affiliation | Hannan, Natalie, University of Melbourne | |
local.contributor.affiliation | George, Amee, College of Health and Medicine, ANU | |
local.contributor.affiliation | Clyne, Colin, Hudson's Institute of Medical Research | |
local.contributor.affiliation | Ernst, Matthias, Olivia Newton-John Cancer Research Institute | |
local.contributor.affiliation | Allen, Andrew, University of Melbourne | |
local.contributor.affiliation | Chand, Ashwini, Hudson's Institute of Medical Research | |
dc.relation | http://purl.org/au-research/grants/nhmrc/1062247 | |
local.bibliographicCitation.issue | 12 | |
local.bibliographicCitation.startpage | 18640 | |
local.bibliographicCitation.lastpage | 18656 | |
local.identifier.doi | 10.18632/oncotarget.15553 | |
dc.date.updated | 2020-11-23T11:14:17Z | |
local.identifier.scopusID | 2-s2.0-85015761799 | |
local.identifier.thomsonID | 000396879200006 | |
dcterms.accessRights | Open Access | |
dc.provenance | https://v2.sherpa.ac.uk/id/publication/25551..."published version can be made open access in any repository" from SHERPA/RoMEO site (as at 23/09/21). | |
Collections | ANU Research Publications |
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