HomeENGLISH MAGAZINEBreast tumor: the oncogene works as multifaceted driver in hormonal pathways

Breast tumor: the oncogene works as multifaceted driver in hormonal pathways

Scientists at VCU Massey Cancer Center have discovered that the loss of a protein called DBC1 in breast cancer cells leads to the dysregulation of normal anti-cancer functions, contributing to cancer cell growth and resistance to therapies. By restoring the expression of this protein, doctors may be able to help prevent the development of cancer and increase the effectiveness of common cancer treatments. Recently published in the journal&nbsp;<em>Cell Reports</em>, the study used mass spectrometry to identify proteins that interact with processes that regulate the gene p53, which normally acts to suppress the development of cancer and has been found to be dysregulated in a majority of cancer types. Researchers screened for proteins that interact with a protein within the nucleus of cells called CREB binding protein (CBP) that is known to regulate the gene p53. They found one of the proteins discovered in this screen called DBC1 is critical to maintaining the levels and activity of p53, and the gene encoding for this protein is frequently deleted in breast cancer cells.

Previous research has shown that the CBP works with another protein known as MDM2 to maintain p53 levels in cells. This latest work shows that DBC1 regulates CBP activity, and therefore plays an essential role in maintaining p53 activity and abundance in normal cells. The scientists used human breast cancer cell lines and mouse models to test their findings. They discovered that DBC1 levels decrease in response to cellular stress, which can be caused by platinum-based cancer drugs, for example. This drop in DBC1 decreased p53 levels, making the cells resistant to p53-mediated apoptosis, a form of controlled cell suicide. Many cancer drugs work by inducing apoptotic cell death. Here, scientists showed that maintaining DBC1 levels in cancer cells exposed to cisplatin, a platinum-based cancer drug, caused a substantially increased response to the drug. This shows that cancer cells have developed finely tuned responses to control DBC1 levels in order to avoid exaggerated apoptotic responses. A variety of cancers shown to have dysregulated DBC1 levels, such as breast, lung and prostate cancers. Therefore, restoring the function of DBC1 could potentially make tumors more susceptible to current cancer treatments and help prevent further cancer growth.

Another team investigated another potential strategy, focusing on the basic nature of breast cancer in connection with the DBC1 protein: the role of estrogens and the estrogen receptor. Estrogen/ERα signaling is critical for breast cancer progression and therapeutic treatments. Thus, identifying new regulators of this pathway will help to develop new therapeutics to overcome chemotherapy resistance of the breast cancer cells. A team from the Shanghai Jiaotong University School of Medicine, report that a protein called Ajuba directly interacts with ERα to potentiate ERα target gene expression, and biologically Ajuba promotes breast cancer cell growth and contributes to tamoxifen resistance of these cells. Ajuba constitutively binds the estrogen receptor, and these interactions can be markedly enhanced by estrogen treatment in vitro. Mechanistically, Ajuba recruits DBC1 and CBP/p300 and forms a ternary complex to co-activate ERα transcriptional activity and concomitantly enhances ERα acetylation. Moreover, components of this complex can be found at endogenous promoters containing functional ERα responsive elements.

Therefore, the role of DBC1 oncogene could be more directly related to hormone-positive breast cancers.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Akande O et al., Grossman SR. Cell Rep. 2019; 26(12):3323.

u B et al., Nucleic Acids Res; 2019 Mar 18; 47(5):2322-2335.

Yu X, Wang M et al. Mol Carcinog. 2018; 57(12):1803-1815.

Dott. Gianfrancesco Cormaci
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (leader of the R&D for the partnership CoFood s.r.l.) - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica e salute sui siti web salutesicilia.com, medicomunicare.it e in lingua inglese sul sito www.medicomunicare.com
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