title: AGTR1 overexpression defines a subset of breast cancer and confers sensitivity to losartan, an AGTR1 antagonist.
abstract: Breast cancer patients have benefited from the use of targeted therapies directed at specific molecular alterations. To identify additional opportunities for targeted therapy, we searched for genes with marked overexpression in subsets of tumors across a panel of breast cancer profiling studies comprising 3,200 microarray experiments. In addition to prioritizing ERBB2, we found AGTR1, the angiotensin II receptor type I, to be markedly overexpressed in 10-20% of breast cancer cases across multiple independent patient cohorts. Validation experiments confirmed that AGTR1 is highly overexpressed, in several cases more than 100-fold. AGTR1 overexpression was restricted to estrogen receptor-positive tumors and was mutually exclusive with ERBB2 overexpression across all samples. Ectopic overexpression of AGTR1 in primary mammary epithelial cells, combined with angiotensin II stimulation, led to a highly invasive phenotype that was attenuated by the AGTR1 antagonist losartan. Similarly, losartan reduced tumor growth by 30% in AGTR1-positive breast cancer xenografts. Taken together, these observations indicate that marked AGTR1 overexpression defines a subpopulation of ER-positive, ERBB2-negative breast cancer that may benefit from targeted therapy with AGTR1 antagonists, such as losartan.
authors.affiliation: Michigan Center for Translational Pathology, Howard Hughes Medical Institute, and Departments of Urology, and Pathology, University of Michigan Medical School, 1301 Catherine Street, Ann Arbor, MI 48109-5602.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Rhodes
authors.forename: Bushra
authors.initials: B
authors.lastname: Ateeq
authors.forename: Qi
authors.initials: Q
authors.lastname: Cao
authors.forename: Scott A
authors.initials: SA
authors.lastname: Tomlins
authors.forename: Rohit
authors.initials: R
authors.lastname: Mehra
authors.forename: Bharathi
authors.initials: B
authors.lastname: Laxman
authors.forename: Shanker
authors.initials: S
authors.lastname: Kalyana-Sundaram
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lonigro
authors.forename: Beth E
authors.initials: BE
authors.lastname: Helgeson
authors.forename: Mahaveer S
authors.initials: MS
authors.lastname: Bhojani
authors.forename: Alnawaz
authors.initials: A
authors.lastname: Rehemtulla
authors.forename: Celina G
authors.initials: CG
authors.lastname: Kleer
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hayes
authors.forename: Peter C
authors.initials: PC
authors.lastname: Lucas
authors.forename: Sooryanarayana
authors.initials: S
authors.lastname: Varambally
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D019808:Losartan / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D019808:Losartan; D044140:Receptor, Angiotensin, Type 1; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human