Molecular Markers for Breast Cancer Susceptibility

摘要

A woman's reproductive history is one of the principal determinants of her susceptibility to breast cancer. This study was based upon the hypothesis that the protective effects of an early pregnancy and lactation result from estrogen(E) and progesterone(P)-induced differentiation and the resultant loss of cells susceptible to carcinogenesis. These effects of E and P are mediated by the induction of specific 'local mediators', i. e. growth factors that act via autocrine and paracrine mechanisms to influence terminal duct(TD) and end BUD(TEB) growth and differentiation. These rapidly proliferating cells are the most susceptible to neoplastic transformation. Thus, the objective of this study was to identify molecular markers for TEB and TD cells in order to follow their fate during mammary development and carcinogenesis. One of the clones identified that was preferentially expressed in the TEB fraction was p190-B a member of the Rho-GAP family of proteins involved in integrin signaling. Higher expression of p190-B was observed in the outer layer of cells of the terminal end bud. In addition, p190-B was highly expressed in approximately 40% of mouse TM and rat NMU-induced mammary tumors. Therefore, p190-B expression may be required for ductal morphogenesis during virgin mammary gland development and its aberrant expression may occur in aggressive tumors. These studies have also resulted in the application of confocal microscopy to study cell cycle kinetics in thick frozen sections,-derived from the mm mammary gland at different stages of development. Finally, a chance finding in the course of the study led to the discovery of supernumerary centrosomes in a variety of human breast tumors that correlated with over-expression of a gene known as breast tumor amplified kinase (BTAK) in 12% of human breast tumors. Antibodies raised against the 46 kDa BTAK peptide tide co-localized with centrosomes. This gene.