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Caveolin‐1 loss in human breast cancer is associated with increased tumor aggressiveness and mortality
Author(s) -
Hart Peter,
Minshall Richard,
Bonini Marcelo
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.284.6
Subject(s) - cancer research , carcinogenesis , biology , caveolin 1 , ectopic expression , breast cancer , medicine , endocrinology , microbiology and biotechnology , cancer , cell culture , genetics
Caveolin‐1 (Cav‐1) is the key component of lipid raft vesicles (caveolae) responsible for transcytosis of molecules, and can directly bind enzymes to regulate cell signaling involved in proliferation and migration. Cav‐1 loss has been associated with tumor progression; however, the mechanisms by which Cav‐1 impacts tumor development are unknown. Tissue micro‐array analysis showed that reduction of Cav‐1 throughout tumor grade is associated with 2‐3 fold increases in Nrf‐2 expression, a transcription factor that induces enzymes such as MnSOD. We had recently shown that overexpression of MnSOD can enhance glycolysis through AMPK activation, thereby driving tumorigenesis. Together, these findings led to the hypothesis that loss of Cav‐1 promotes MnSOD overexpression through increased Nrf‐2 transcriptional activity. Epidemiological studies revealed that low Cav‐1 and high MnSOD were both independently associated with decreased 5‐year survival. Stratification of this cohort by low Cav‐1 and high MnSOD together showed a marked increase in mortality (odds ratio, OR = 1.576, 95% CI 1.076 – 2.307, p < 0.05) as well as aggressive disease such as triple negative status (OR = 2.099, 95% CI 1.321 – 3.333, p < 0.005). These clinical findings were evaluated using mechanistic approaches in which Cav‐1 ectopic expression in cells devoid of Cav‐1 (MCF‐7) was sufficient to repress Nrf‐2 and MnSOD expression, inhibit glycolysis, and reduce invasiveness of these cells. Taken together, Cav‐1 loss and the associated increase in MnSOD expression may provide a novel prognostic biomarker for risk stratification in patients with invasive ductal carcinoma.