Molecular Rationales for Signal Transduction Therapy and Chemoprevention of BRCA1-Related Breast and Ovarian Tumours

P.      Tagliaferri; P.      Tassone; A.      Pietragalla; M.   S.   Rotundo; V.      Barbieri; A.      Budillon; M.      Caraglia; F.   S.   Costanzo; S.      Venuta

Abstract

The design of novel therapeutic strategies based on tumour molecular features and specific carcinogenetic pathways is a compelling issue. Tumours arising in BRCA1-defective individual carriers constitute a specific entity which resembles the basal-like molecular phenotype for breast tumours, while BRCA1-defective ovarian cancer has a molecular signature which is also shared by a substantial amount of sporadic tumours. Several important issues are derived from the role of BRCA1 gene product in critical cell functions like DNA repair, transcription regulation and cell cycle checkpoint control. It has been recently demonstrated that the loss of such functions in BRCA1-defective tumours results in a specific profile of sensitivity to anti-cancer drugs. Moreover, BRCA1 appears to retain a critical role in the response of cells to stress as well as to the growth promoting stimuli generated by estrogens and peptide growth factors. Therefore, it is conceivable that loss of a functional BRCA1 produces a general de-arrangement of cellular signaling which might allow the identification of specific and high priority targets and lead to individualized signal transduction-based anti-tumour approaches. We will review the most important findings related to BRCA1 effects on cellular signaling in order to depict a general scenario for selective chemopreventive and therapeutic strategies.

Keywords: Hereditary cancer, breast cancer, ovarian cancer, BRCA1, signal trasduction, prevention, targeted therapy