Cooperative Interactions During Human Mammary Epithelial Cell Immortalization
Final rept. 1 Jul 2002-30 Jun 2005
CALIFORNIA UNIV BERKELEY
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Our laboratories have developed and utilized cultured human mammary epithelial cells HMEC to gain information on the defects in growth control processes that allow finite lifespan HMEC to overcome all senescence barriers, reactivate telomerase, and gain immortal potential. We hypothesize that, due to the stringency of telomerase repression in humans, attaining these defects may be rate-limiting in human carcinogenesis. Our goal is to define the minimum number of genetic and epigenetic changes that permit telomerase reactivation and immortal transformation of finite lifespan HMEC, in a manner that models changes observed in breast cancers. Thus far, we have been able to obtain immortalized HMEC using combinations of oncogenes with pathological relevance to human breast cancer. Although CGH analyses of some of these immortal lines did not show any detectable large- scale changes in gene copy numbers, these lines have all undergone clonal selection, suggesting that additional unknown stochastic changes are necessary for immortalization. These additional changes remain to be discovered. The exact nature of these alterations may vary depending upon the differentiationepigenetic state of the targeted cells. Better understanding of the underlying molecular changes involved in telomerase reactivation may provide novel prevention strategies andor targets for therapeutic intervention in breast cancer pathogenesis.
- Anatomy and Physiology
- Medicine and Medical Research
- Stress Physiology