AGTR1 overexpression defines a subset of breast cancer and confers sensitivity to losartan, an AGTR1 antagonist.
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.
Rhodes
Daniel R
DR
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.
Ateeq
Bushra
B
Cao
Qi
Q
Tomlins
Scott A
SA
Mehra
Rohit
R
Laxman
Bharathi
B
Kalyana-Sundaram
Shanker
S
Lonigro
Robert J
RJ
Helgeson
Beth E
BE
Bhojani
Mahaveer S
MS
Rehemtulla
Alnawaz
A
Kleer
Celina G
CG
Hayes
Daniel F
DF
Lucas
Peter C
PC
Varambally
Sooryanarayana
S
Chinnaiyan
Arul M
AM
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
D047228:Angiotensin II Type 1 Receptor Blockers; D019808:Losartan; D044140:Receptor, Angiotensin, Type 1; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human