Molecular mechanisms of triple negative and basal-like breast cancers.

摘要

Breast cancer is a complex disease consisting of molecular subtypes that have different clinical outcomes. While the basal-like subtype accounts for only a small subset of all breast cancer cases, it is associated with the worst prognosis and is overrepresented in young women and women of African ancestry. Basal-like tumors are triple negative (ER-, PR-, and HER2-negative), and the majority of triple negative tumors are of a basal-like phenotype. The molecular drivers of the basal-like phenotype have not yet been identified, and there is a lack of targeted therapies for women with this tumor subtype. To identify potential molecular markers and/or pathways that are critical to the triple negative and basal-like tumor phenotype, I investigated two molecular mechanisms, epigenetic regulation of BRCA1 and dysregulation of microRNAs. The association of BRCA1 promoter methylation with the development of sporadic triple negative (TN) and basal-like tumors was examined in 198 primary human breast samples using methylation specific PCR (MSP). BRCA1 inactivation via promoter methylation occurred in half of the sporadic TN and basal-like tumors and may be an early event, similar to BRCA1 inactivation by mutation, in the development of a subset of these tumor types. These findings justify the use of PARP inhibition, which have proven beneficial for hereditary breast cancers, for treatment and/or prevention of sporadic BRCA1-deficient TN and basal-like breast cancers.;Furthermore, differential expression of microRNAs in sporadic triple negative and basal-like tumors was examined using a microRNA expression array. Forty-four microRNAs were identified as down-regulated in basal-like tumors compared to luminal A tumors, and microRNA-29c, the most significantly down-regulated microRNA, was capable of regulating some phenotypes associated with basal-like tumors (e.g. cell invasion and drug resistance). microRNA-29c also regulates B-MYB levels and this regulation involves the B-MYB 3'UTR. Furthermore, microRNA-29c sensitizes cells to doxorubicin-induced killing through regulation of B-MYB, an oncogene over-expressed in basal-like tumors. This work represents the first study to functionally characterize the role of miRNAs in basal-like breast tumors, as well as identify B-MYB as a bonafide miR-29c target. My findings suggest that inhibition of B-MYB or over-expression of miR-29c may be clinically beneficial for patients with basal-like tumors.