Abstract
The concept that human cancer is in essence a genetic disease driven by gene mutations has been well established, yet its utilization in functional studies of cancer genes has not been fully explored. Here, we describe a simple genetics-based approach that can quickly and sensitively reveal the effect of the alteration of a gene of interest on the fate of its host cells within a heterogeneous population, essentially monitoring the genetic selection that is associated with and powers the tumorigenesis. Using this approach, we discovered that loss-of-function of TP53 can promote the development of resistance of castration in prostate cancer cells via both transiently potentiating androgen-independent cell growth and facilitating the occurrence of genome instability. The study thus reveals a novel genetic basis underlying the development of castration resistance in prostate cancer cells and provides a facile genetic approach for studying a cancer gene of interest in versatile experimental conditions.
Highlights
Germline or somatic mutations occur constantly at a measurable rate in the human body[1,2,3]
Mutations providing proliferation/survival advantage to their host cells can achieve expansion, in which the host cells propagate, shift the balance, and eventually become clonal, or sub-clonal such that it is feasible for them to be identified as cancer genes[4]
Two applications that arise from this conception are: (i) decoding of the human cancer genome that leads to identification of most, if not all, critical genes whose mutations drive the development of human cancer, an area of research that has been extremely important and fruitful[4,5]; and (ii) a challenging task of functional studies of cancer genes via genetically modifying them in appropriate experimental contexts[6,7,8]
Summary
Germline or somatic mutations occur constantly at a measurable rate in the human body[1,2,3]. Two applications that arise from this conception are: (i) decoding of the human cancer genome that leads to identification of most, if not all, critical genes whose mutations drive the development of human cancer, an area of research that has been extremely important and fruitful[4,5]; and (ii) a challenging task of functional studies of cancer genes via genetically modifying them (i.e., recapitulating their alterations in cancers) in appropriate experimental contexts[6,7,8] This latter implication, frequently via somatic gene targeting, has become an increasingly common pursuit, largely powered by new genome editing technologies such as CRISPR6,9. We describe such a genetic approach and use it to reveal the unique role of TP53’s loss-of-function in the development of castration-resistant prostate cancer (CRPC)
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