Exploiting Senescence for Breast Cancer Prevention and Treat
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: Non-technical overview of the research topic and relevance to breast cancer: Despite the recent success of “targeted drugs”, 
 
 
 
 traditional chemotherapy, which acts broadly to kill cells, is still the drug of choice for triple-negative breast cancers (TNBCs). However, 
 
 
 
 chemotherapy is highly toxic and causes severe side effects for patents. There is an urgent need in breast cancer treatment to replace 
 
 
 
 interventions with life threatening toxicities with ones that are safe and effective. We have been exploring potentially new therapeutic 
 
 
 
 approaches for TNBC treatment that exploit the “natural” processes present within all cells. Senescence, which is a state of 
 
 
 
 irreversible quiescence, is one such process. In normal breast cells, senescence acts a crucial barrier against cancer development. The 
 
 
 
 activation of oncogenes or inactivation of tumor suppressor genes triggers senescence, which promotes the irreversible growth arrest of pre-
 
 
 
 malignant cells and their subsequent eradication from the body. In order for breast cancers to fully develop, a premalignant breast cell must 
 
 
 
 somehow acquire the ability to overcome the senescence barrier and then maintain an anti-senescent state. However, very little is known about how 
 
 
 
 these processes are controlled. In our preliminary studies, we sought to identify the genes that are required for breast cancer cells to maintain 
 
 
 
 an anti-senescent state. We used an innovative cell image-based functional screening approach and identified a largely uncharacterized enzyme 
 
 
 
 called Fbxo44 as a crucial determinant in this process. Knockdown of Fbxo44 expression in all breast cancer cell lines tested, including TNBCs 
 
 
 
 and the aggressive chemotherapy resistant claudin-low TNBC sub-type, induced profound irreversible senescence, suggesting that breast cancer 
 
 
 
 cells are “addicted” to Fbxo44 for their continued growth. Importantly, we found that Fbxo44 inhibition was even capable of inducing 
 
 
 
 senescence in TNBC cells deficient in p53, pRb, or BRCA1, which are the major senescence regulations in breast cells and important determinants of 
 
 
 
 TNBC aggressiveness. Our additional studies showed that Fbxo44 might function by regulating key enzymes involved in DNA synthesis and chromatin 
 
 
 
 epigenetics; processes intricately linked with cellular senescence. 
 
 
 
 
 
 The question(s) or central hypotheses of the research: Targeted inhibition of Fbxo44 could be a powerful therapeutic approach for eradicating 
 
 
 
 TNBCs through the novel mechanism of induced cellular senescence. Because Fbxo44 functions independent of p53, pRb, and BRCA1, this “pro-
 
 
 
 senescence” therapy could be effective against even the most aggressive TNBCs, including claudin-low cancers which are generally resistant 
 
 
 
 to chemotherapy. In addition, Fbxo44 targeted inhibitors are expected to display significantly reduced toxicity compared to conventional 
 
 
 
 chemotherapy since they exploit a natural process common to all cells in the body.
 
 
 
 
 
 The general methodology: We will use molecular and biochemical approaches to elucidate the molecular mechanism(s) by which Fbxo44 inhibition 
 
 
 
 promotes senescence of TNBC cells. This will include an examination of Fbxo44’s putative role in controlling chromatin modifications. We 
 
 
 
 will also evaluate the effects of Fbxo44 inhibition on inducing senescence of TNBC stem cell/tumor-initiating cells (TICs). Finally, we will use a 
 
 
 
 mouse breast cancer model to evaluate the therapeutic potential of Fbxo44 inhibitors in preventing the growth of TNBC stem/TICs in vivo 
 
 
 
 and tumorigenicity of chemotherapy resistant claudin-low TNBCs, through the mechanism of induced senescence. 
 
 
 
 
 
 Innovative elements of the project: 1) The concept of exploiting the senescence program for breast cancer/TNBC treatment is highly 
 
 
 
 novel and no current cancer drug is known to function via this mechanism; 2) Fbxo44 represents the only senescence pathway identified to 
 
 
 
 date that functions independent of the crucial senescence effectors p53, pRb, and BRCA1, suggesting that cancers defective in these genes will be 
 
 
 
 susceptible to Fbxo44-targeted inhibition; and 3) Since stem/TICs are susceptible to senescence, Fbxo44 inhibition offers a potentially 
 
 
 
 highly effective therapeutic approach for eradicating the cancer stem/TIC component of TNBCs, thereby preventing these cancers from recurring 
 
 
 
 and/or metastasizing, for which no other therapy has been shown effective. 
 
 
 
 
 
 
 
 Publications: 
 
 
 
 F-box proteins in epigenetic regulation of cancer