Targeting Prolactin as a Novel Treatment for Breast Cancer
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: A number of growth factor and hormone receptors and signaling molecules have natural “dominant negative” varieties, formed by “alternative splicing” of a single gene transcript. Genes are transcribed to produce pre-mRNAs, which are then spliced to create the mature mRNAs translated into protein. In the last few years, deep sequencing and microarray analyses have shown greater than 90% of human pre-mRNAs undergo alternative splicing, thereby amplifying the potential protein products from each gene. Alternatively spliced forms of pre-mRNA may code for proteins with related, distinct, or even opposing functions (dominant negatives). To our knowledge no one has previously tapped the potential of natural dominant negatives to combat disease in general, and breast cancer in particular. Researchin my laboratory is concerned with the growth factor activities of the hormone prolactin. These growth factor activities occur in many tissues including the pituitary, breast, endocrine pancreas, liver, prostate, and cells of the immune system. Although most prolactin is produced by the pituitary, some is produced in these other tissues where it may act as an autocrine (hormone or chemical messenger binding to the same cell) or paracrine (nearby cell) growth factor.
 
 
 
 
 
 There is evidence that “upregulation” of the dominant negative version of prolactin will affect survival of cancer stem cells and prevent tumor angiogenesis. We will begin by examining the effects of our designed “splice modulating oligomers” (i.e., short, 20 nucleotide chains that bind to pre-mRNA and cause changes in splicing) on human and mouse breast cancer cells grown in culture. We will compare the effects of oligomers targeting the human and mouse receptors for their effects on cell proliferation, migration, invasion, cell death and the number of stem cells. If the effects are comparable in human and mouse cells, we will examine effects of the oligomers on tumors of mouse cells in normal mice. In this way, we can examine effects in an animal with a normal immune system using a model system that accurately recapitulates progression of the human disease. If the human and mouse cells do not respond equivalently, we will instead examine the effects of the oligomers on human tumors grown in mice without a normal immune system. It is necessary for mice in this instance to be immuno-compromised so that they will allow tumors of human cells to grow. At the same time in the animal experiments, we will examine the mice for potential unexpected side effects and toxicities.
 
 
 
 
 
 In addition to the prolactin receptor, potential targets of this class of oligomer drugs include receptors for estrogen and growth hormone, each of which has been shown to have a dominant negative variety formed by alternative splicing. Other targets exist, and as we learn more about the basic biology of breast cancer, it is likely that many more targets will appear. An attractive feature of the splice modulating oligomers is that they can be combined to target more than one receptor or signaling molecule or transcription factor at a time, thereby potentially increasing the impact of treatment and reducing the possibility that cells can become resistant.