HomeENGLISH MAGAZINEBreast cancER using rogue codes: would you BET epigenome is the key...

Breast cancER using rogue codes: would you BET epigenome is the key for its defeat?

Luminal-A breast cancer responds well to estrogen receptor alpha (ERα) antagonist drugs, the best known of which is tamoxifen. Through this protein, estrogen drives malignant cell replication that leads to tumor expansion. Not all breast cancers are, however, positive for the presence of ER-alpha. Some subtypes do not express it at all and often this also happens for progesterone receptors (PR-alpha) and those for epidermal growth factor (Her-2/EGFR). In the first case, ER-negative tumors develop while in the second case, the triple-negative variants, which are the most malignant and aggressive. Initially it was believed that it was not possible to intervene on the more aggressive forms and that, in one way or another, they could lead patients to a fatal outcome. With the knowledge coming from epigenetics, the conclusion has been reached that it is possible to manipulate certain pathways of the genetic code in order to be able to reverse certain cellular behaviours.

A well-known method, studied and used for this purpose is to manipulate the acetylation of histones attached to DNA, in order to influence gene expression. Histone deacetylase enzymes HDAC 1 and 2 modify DNA-associated histones into a less accessible conformation. Through this modification the target gene is not transcribed and “gene silencing” is obtained. To reverse this process, research has developed selective HDAC inhibitors, some of which have passed clinical trials and are already being used in clinical practice, alone but more commonly to make other chemotherapies more effective. The best known are givinostat, vorinostat and panabinostat. Treatment with HDAC inhibitors allows the missing receptors to be expressed again and this allows clinicians to use their classic antagonists in chemotherapy, such as the aforementioned tamoxifen and other more recent receptor modulators such as raloxifene and arzoxifene.

Paradoxically, in ER+ human breast cancer cell lines, HDAC inhibitors promote transcriptional down-regulation of estrogen receptors and their responsive genes, whereas in ER-negative cells, HDAC inhibitors can re-establish the expression of the receptors and re-sensitize them to anti-oestrogens. For example, receptors can be restored in MDA-MB-231 and MDA-MB-435 cells (triple-negative variants) by the inhibitor LBH589, demonstrating that chromatin reorganization plays a role in the loss of these receptors. In xenografts of MCF-7 cells resistant to aromatase inhibitors such as letrozole, the HDAC inhibitor entinostat restores letrozole sensitivity by modulating Her-2 expression and activity. But it is not only triple-negative tumors that cause the greatest clinical and therapeutic problems. Even regular hormone sensitive (ER+) breast cancers can go the “bad route” of converting to ER-negative forms.

For patients with estrogen receptor (ER) positive breast cancer, the development of the so-called Y537S mutation signals that their disease has taken an aggressive course and may become resistant to endocrine therapy. Now a preclinical study, led by researchers at UT Southwestern Medical Center, suggests that a class of new drugs already in clinical trials may work particularly well in breast cancer patients who have acquired this mutation. By testing more than 1,200 existing drugs or drug candidates against breast cancer cells, the researchers identified a BET inhibitor called OTX015 that significantly suppressed the growth of breast cancer cells, particularly those carrying the Y537S mutation. BET proteins are widely recognized as major transcriptional regulators in biology. They are characterized by internal domains that bind to lysine-acetylated histones and transcription factors, recruiting transcription factors and coactivators to target gene sites.

Small molecules targeting BET domains are tested for various diseases but do not distinguish between BET proteins. Studies have highlighted context-specific, distinct and often opposing functions of BRD2, BRD3, BRD4 and BRDT. For example, distinct roles of BET proteins in ERα-enhancing function and gene regulation have been demonstrated in breast cancer cells. While BRD2, BRD3 and BRD4 have partially redundant roles in ERα enhancers and gene transcription, a more unique role of BRD3 in ER+ breast cancer is revealed. BRD3 is recruited to a subset of enriched ER binding sites, which likely function as super-enhancers of highly estradiol-sensitive genes. In phase 1 OTX015 proved to be quite safe and easy to handle. The drug also showed high efficacy in inhibiting the growth of tumors harboring Y537S mutations when implanted in mice.

Additionally, when combined with abemaciclib, an anti-resistance drug approved for the treatment of breast cancer patients, OTX015 showed greater efficacy in inhibiting tumor growth than existing standard of care treatment. Therefore, targeting BET proteins has the potential to both prevent and overcome ER mutant-induced anti-endocrine resistance in breast cancer. Lesser toxicity of novel molecules, compared to older chemodrugs, makes them more attractive than ever.

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

Scientific references

Udden SN et al JCI Insight 2022 Sep; 7(17):e151851.

Hanker AB et al. Cancer Cell. 2020; 37(4):496-513.

Choi SR et al. Cancer Res. 2022 Jan; 82(2):320-333.

Nardone A et al. Br J Cancer. 2019; 120(3):331-339.

Casey AE et al. J Cell Biol. 2018; 217(8):2951-2974.

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- 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 enzimaticamente 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 articoli su informazione medica e salute sul sito www.medicomunicare.it (Medical/health information on website) - Autore di corsi ECM FAD pubblicizzati sul sito www.salutesicilia.it
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