One of the main challenges in more effectively treating triple-negative breast cancer (TNBC) is the acquisition of resistance to conventional chemotherapeutics. Research led by Sandra Peiró, Principal Investigator of VHIO’s Chromatin Dynamics in Cancer Group, recently published ahead of print and open access in Oncogene*, promises novel weaponry to more effectively combat cancer drug resistance in this particular tumor type.
This multi-center, Spanish study shows that, when compared to other breast cancer subtypes, the DNA of TNBC cells is much more compacted which renders it resistant to therapy. Results also indicate that chromatin decompaction could help to potentiate current therapies.
More specifically, the investigators have identified oxidation of histone H3 as a key element in the induction of DNA compaction as well as discovered an association between compaction and resistance to anticancer agents.
Commenting for VHIO Communications Sandra observed, “This makes it more difficult for drugs whose mechanism of action is based on inducing DNA damage to access tumor DNA, and consequently causes resistance to this type of treatment.”
They also discovered that LOXL2 inhibition could prevent chromatin compaction from occurring. This is particularly relevant since this compaction seems to frequently occur in TNBC, which hinders therapies from accessing the nucleus of cancer cells. “While this occurs in other types of breast cancer, we’ve found that in those patients with the triple-negative subtype who show most resistance to conventional therapies, LOXL2 is present in high quantities, suggesting its role as a mechanism of resistance,” explained Sandra, Corresponding Author of this research.
Inhibiting LOXL2
Although only tested thus far in cell lines and patient-derived xenografts (PDXs), their data suggest that inhibition of LOXL2 in combination with conventional chemotherapy could significantly improve the treatment of TNBC.
In order to pursue this current line of research and, in the absence of any LOXL2 inhibitor, Sandra’s team used azacitidine, an agent which drives DNA demethylation and cranks it open. While this mechanism is not related in any way to LOXL2, it is similar in terms of chromatin decompaction.
“The possible development of a specific agent to act against the nuclear activity of LOXL2 would enable us to target and tackle the origin of the problem as well as ultimately improve outcomes for these patients,” she concluded.
This study was carried out in collaboration with investigators at the Universitat Pompeu Fabra (UPF – Barcelona), including David Andreu, the Department of Experimental Sciences and Health, Travis Stracker from the Institute for Research in Biomedicine (IRB – Barcelona), and VHIO´s Growth Factors Group led by Joaquín Arribas, Co-Program Director of Preclinical & Translational Research at VHIO, ICREA Professor, and Scientific Director of the Spanish CIBERONC Network of Biomedical Research Centres in Cancer.
Sandra Peiró’s Lab is mainly supported by funding received from ”la Caixa” and the Fero Foundation. This particular line of research was also supported by other funding entities including the Instituto Salud Carlos III (ISCIII), Fundació de La Marató de TV3, and the Spanish Association against Cancer (Asociación Española Contra el Cáncer – AECC).
###
Reference:
* Cebrià-Costa JP, Pascual-Reguant L, Gonzalez-Perez A, Serra-Bardenys G, Querol J, Cosín M, Verde G, Cigliano RA, Sanseverino W, Segura-Bayona S, Iturbide A, Andreu D, Nuciforo P, Bernado-Morales C, Rodilla V, Arribas J, Yelamos J, de Herreros AG, Stracker TH, Peiró S. LOXL2-mediated H3K4 oxidation reduces chromatin accessibility in triple-negative breast cancer cells.Oncogene. 2019 Aug 28. doi: 10.1038/s41388-019-0969-1.
