Abstract
BackgroundObesity induces molecular changes that may favor tumor progression and metastatic spread, leading to impaired survival outcomes in breast cancer. Adenylate cyclase-associated protein 1 (CAP1), an actin regulatory protein and functional receptor for the obesity-associated adipokine resistin, has been implicated with inferior cancer prognosis. Here, the objective was to investigate the interplay between body composition and CAP1 tumor expression regarding breast cancer outcome through long-term survival analyses.MethodsAmong 718 women with primary invasive breast cancer within the large population-based prospective Malmö Diet and Cancer Study, tumor-specific CAP1 levels were assessed following thorough antibody validation and immunohistochemical staining of tumor tissue microarrays. Antibody specificity and functional application validity were determined by CAP1 gene silencing, qRT-PCR, Western immunoblotting, and cell microarray immunostaining. Kaplan-Meier and multivariable Cox proportional hazard models were used to assess survival differences in terms of breast cancer-specific survival (BCSS) and overall survival (OS) according to body composition and CAP1 expression.ResultsStudy participants were followed for up to 25 years (median 10.9 years), during which 239 deaths were observed. Patients with low CAP1 tumor expression were older at diagnosis, displayed anthropometric measurements indicating a higher adiposity status (wider waist and hip, higher body mass index and body fat percentage), and were more prone to have unfavorable tumor characteristics (higher histological grade, higher Ki67, and estrogen receptor (ER) negativity). Overall, patients with CAP1-low tumors had impaired BCSS (adjusted hazard ratio: HRadj = 0.52, 95% CI 0.31–0.88) and OS (HRadj = 0.64, 95% CI 0.44–0.92) compared with patients having high CAP1 tumor expression. Further, analyses stratified according to different anthropometric measures or ER status showed that the CAP1-associated survival outcomes were most pronounced among patients with low adiposity status or ER-positive disease.ConclusionsLow CAP1 tumor expression was associated with higher body fatness and worse survival outcomes in breast cancer patients with effect modification by adiposity and ER status. CAP1 could be a novel marker for poorer survival outcome in leaner or ER-positive breast cancer patients, highlighting the need for considering body constitution in clinical decision making.
Highlights
Breast cancer is the most common female malignancy worldwide with around two million new diagnoses annually [1]
The specificity of the antibody was determined by applying a genetic strategy of siRNAmediated cyclase-associated protein 1 (CAP1) gene knockdown. Quantitative reverse transcription PCR (qRT-PCR) analyses confirmed an efficient CAP1 knockdown with 6 and 2% detectable mRNA expression in T47D and MDA-MB231 cells, respectively, compared with the non-silencing controls
In summary, our results demonstrate that lower CAP1 protein expression in early breast cancer was linked to higher adiposity status, more aggressive disease characteristics, and reduced long-term survival in women with breast cancer
Summary
Breast cancer is the most common female malignancy worldwide with around two million new diagnoses annually [1]. The adipose tissue, recognized as an endocrine organ, secretes local and systemic bioactive adipokines with implications for tumor development [10]. Among these adipokines, circulating resistin levels have been reported to be positively correlated with obesity and incidence of postmenopausal breast cancer [11,12,13,14]. High levels of resistin in breast cancer tissue have been linked to more advanced tumor stage with large tumor size and lymph node involvement, positive estrogen receptor (ER) status, and poor breast cancer outcome [16]. The objective was to investigate the interplay between body composition and CAP1 tumor expression regarding breast cancer outcome through long-term survival analyses
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