Loss of constitutive ABCB1 expression in breast cancer associated with worse prognosis

Abstract

ABCB1 gene encodes an adenosine 5’-triphosphate-binding cassette transporter, which not only confers multidrug resistance phenotype in malignant cells, but is also present in several nonmalignant tissues. For the last thirty years, ABCB1 expression in breast cancer has been described by many authors, but the extent of expression differs among the studies, and there is no consensus regarding its potential role in carcinogenesis or in the tumor response to antineoplastic drugs. This study aimed to characterize the expression of ABCB1 in breast tumors as a function of genetic, clinical, and histopathological variables. The ABCB1 expression was also evaluated in nonmalignant mammary tissues adjacent to tumors and in benign lesions. The detection of ABCB1 protein was performed by immunohistochemistry in tissue specimens of excised breasts obtained from a prospective cohort of Brazilian women with breast cancer. The association of ABCB1 protein levels with ABCB1 mRNA, gene polymorphisms, and clinical and histopathological variables was also evaluated. The Kaplan-Meier curves and multivariate Cox regression analyses were conducted to identify independent predictors of disease-free survival of patients with breast cancer. ABCB1 was detected in 86.3% (656) of breast tumors, 98.8% (606) of nonmalignant mammary tissue adjacent to tumors, and 100% (28) of benign lesions. Reduced ABCB1 protein levels in breast tumors was associated with triple-negative subtype (adjusted odds ratio [ORadj] = 0.24; 95% confidence interval [CI] =0.13-0.45), lymph node status 2 cm (ORadj =0.55; 95% CI =0.32-0.93), and hypertensive status (ORadj =0.42; 95% CI =0.24-0.73), and it was significantly associated with shorter disease-free survival, either for all breast cancer patients (p log-rank =0.012; hazard ratio [HR] =3.46; 95% CI =1.21-9.91) or for those with triple-negative tumors (p log-rank =0.007; HR =11.41; 95% CI =1.29-100.67). The loss of constitutive ABCB1 expression in breast cancer, especially in triple-negative tumors, seems to indicate a subgroup of worse prognosis.