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The biguanides metformin and phenformin inhibit angiogenesis, local and metastatic growth of breast cancer by targeting both neoplastic and microenvironment cells
Author(s) -
Orecchioni Stefania,
Reggiani Francesca,
Talarico Giovanna,
Mancuso Patrizia,
Calleri Angelica,
Gregato Giuliana,
Labanca Valentina,
Noonan Douglas M.,
Dallaglio Katiuscia,
Albini Adriana,
Bertolini Francesco
Publication year - 2014
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.29193
Subject(s) - phenformin , metformin , biguanide , angiogenesis , cancer research , medicine , in vivo , neovascularization , metastasis , cancer , pharmacology , endocrinology , biology , diabetes mellitus , microbiology and biotechnology
The human white adipose tissue (WAT) contains progenitors with cooperative roles in breast cancer (BC) angiogenesis, local and metastatic progression. The biguanide Metformin (Met), commonly used for Type 2 diabetes, might have activity against BC and was found to inhibit angiogenesis in vivo . We studied Met and another biguanide, phenformin (Phe), in vitro and in vivo in BC models. In vitro , biguanides activated AMPK, inhibited Complex 1 of the respiratory chain and induced apoptosis of BC and WAT endothelial cells. In coculture, biguanides inhibited the production of several angiogenic proteins. In vivo , biguanides inhibited local and metastatic growth of triple negative and HER2+ BC in immune‐competent and immune‐deficient mice orthotopically injected with BC. Biguanides inhibited local and metastatic BC growth in a genetically engineered murine model model of HER2+ BC. In vivo , biguanides increased pimonidazole binding (but not HIF‐1 expression) of WAT progenitors, reduced tumor microvessel density and altered the vascular pericyte/endothelial cell ratio, so that cancer vessels displayed a dysplastic phenotype. Phe was significantly more active than Met both in vitro and in vivo . Considering their safety profile, biguanides deserve to be further investigated for BC prevention in high‐risk subjects, in combination with chemo and/or targeted therapy and/or as post‐therapy consolidation or maintenance therapy for the prevention of BC recurrence.