Breast Cancer Chemoprevention by Retinoids
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: Natural retinoids (vitamin A derivatives) and their synthetic analogs can prevent the development of breast cancer in animal models. Several retinoids are now being evaluated for their ability to prevent breast cancer recurrence in patients at risk. These retinoids can inhibit the growth of cancer cells or cause them to undergo a type of cell death (apoptosis) in which their genetic material is degraded. Although one of these retinoids showed promising activity against breast cancer development in pre-menopausal women in a recent clinical trial, most retinoids either do not prevent the appearance of more malignant breast cancers that have lost their dependence on estrogens for growth or must be given at such high doses to prevent new tumors that they are toxic to patients. The antiestrogen tamoxifen is in clinical use to prevent new tumors, but patients whose tumors are originally inhibited may only respond for 2 to 5 years, after which more aggressive tumors can appear. Therefore, more effective compounds for prevention of breast cancer are urgently needed.
 
 
 
 
 
 
 
 Our proposed project will focus on identifying retinoids to prevent breast cancer development in both pre-menopausal and post-menopausal women. The research will be based on molecular and cellular mechanistic studies of how retinoid effects are mediated through the retinoid receptors (RAR a, b, and g and RXR a, b, and g) to develop retinoids that can inhibit the growth of both estrogen-dependent and -independent breast cancer cells. Our team of molecular and cancer biologists and chemists has exciting preliminary results on retinoids that we are investigating for prevention and treatment of breast cancer through their interactions with retinoid receptors in cells. We found that the natural retinoids can induce RARb and cell death in estrogen-dependent breast cancer cells that express high levels of RARa. Although they had little effect on the more malignant, estrogen-independent breast cancer cells due to low RARa levels in the cells, we discovered that several RXR-selective synthetic retinoids, when used together with RAR-selective retinoids, can effectively induce RAR a and cell death of the cells, probably through a different retinoid signaling pathway. In addition, we have identified a number of other novel RAR selective retinoids that alone can effectively induce cell death in both breast cancer cell types. Very recently, we found that retinoid receptors can interact with Bag-l, a gene that prevents cell death, thereby providing an opportunity to develop retinoids that selectively promote receptor/Bag-1 interaction and induce apoptosis. We will build on these results to (1) gain a better understanding of how retinoids and their receptors prevent breast cancer development and (2) identify improved retinoids as breast cancer preventive agents.
 
 
 
 
 
 
 
 We propose to identify how these retinoids exert their anti-breast cancer effects and then adapt these mechanisms to identify more effective retinoids. We will first study how retinoids, on binding to their receptors in both estrogen-dependent and -independent breast cancer cells, induce the synthesis of RARb, which is lost or inactivated when cells become cancerous. We will analyze the effects of these retinoids on RARb activities and induction of Bag-1 to clarify their mechanisms of action. These results will enable us to design and prepare more selective retinoids with enhanced cancer preventive activity, which will then be evaluated in molecular and cellular assays for breast cancer cell growth inhibition and cell death induction. The most effective and selective retinoid found in this assay, and two modified versions that permit it to concentrate in breast tissue, will be evaluated for breast cancer prevention in the rat. The outcome of our improved understanding of how retinoids prevent breast cancer development should lead to identifying more effective retinoids to prevent this devastating disease in California residents.