CDRI scientist finds out a novel option to tackle Triple-Negative Breast Cancer metastasis

New Delhi: India is known as the Triple-Negative Breast Cancer (TNBC) capital of the world owing to its high incidence. TNBC is the deadliest amongst all breast cancer subtypes with few therapeutic options. This type of cancer is associated with early metastasis resulting in poor five-year survival rates.

Dr Dipak Datta’s research group at CSIR-CDRI has recently published an article in a peer reviewed international journal, Nature Communications 13, 7344 (2022), that uncovers new functions for epigenetic modulator EZH2 (Enhancer of Zeste homolog 2) in the spread (metastasis) of TNBC. (An epigenetic modulator regulates whether a gene will be expressed or not).

Using an inhibitor of EZH2,  Tazemetostat, Dr Datta and team have demonstrated a new and interesting mechanism for EZH2 mediated gene upregulation that can dictate TNBC progression. In contrast to its classical role in suppressing gene expression, the team found that EZH2 can mediate the overexpression of specific genes, promoting the spread of cancer from the breast to liver and spleen in animal models of TNBC. These findings suggest a rationale for targeting TNBC with EZH2 inhibitors.

Considering annual incidence, breast cancer now ranks first among Indian women. It is a very heterogeneous disease with multiple subtypes. Presence of three different hormone/growth factor receptors (viz., Estrogen Receptor or ER, Progesterone Receptor or PR and Human Epidermal Growth Factor Receptor 2 or HER2) majorly determine breast cancer subtypes and treatment modalities. Anti-hormone/HER2 therapies work in most of such cases, however, there is another subtype, that lacks the overexpression of all three receptors, known as Triple Negative Breast Cancer or TNBC. TNBC is the deadliest among all breast cancer subtypes as conventional targeted therapies do not work. Further, rather unfortunately, India is known to be the TNBC capital of the world due to its highest incidence.

Metastasis or tumor spread to the distant organs is responsible for 90% patient mortality and morbidity. TNBC metastasizes or spreads faster than other breast cancer subtypes resulting in poor 5-year survival rate, following diagnosis. We do not know much about the molecular details of how TNBC metastasizes. In this study, we set out to identify the molecular processes that are responsible for the spread of TNBC. Our studies reveal that hyperactivation of EZH2 is critical in the spread from breast to liver and spleen (peritoneal metastasis). Mechanistically, we have excavated that instead of the classical suppressive function, EZH2 functional activation can promote specific gene expression, like KRT14 to govern the TNBC peritoneal metastasis. Finally, we identify that the EZH2 inhibitor drug Tazemetostat (EPZ6438) can be a promising therapeutic option against the most aggressive TNBC, where targeted therapy is still an enigma.

Need and significance of this study

As stated earlier, the incidence of TNBC is higher (18-31%) in India compared to other regions of the world (8-15%). These figures are alarming. The high rate of TNBC in India is linked to several risk factors, the most important of which are lifestyle changes, obesity, a family history of the disease, a high mitotic index, and BRCA1 gene mutations. Another important aspect is that TNBC is more prevalent among younger women. It is very aggressive, metastasises early with high recurrence rate and poor five-year survival rates. Unlike other types of cancer for which therapies that specifically target the mutated pathways exist (targeted therapies), for TNBC, routine chemotherapy is the only treatment option. Such therapies are associated with a number of side effects such as tiredness, hair loss, anaemia etc. Moreover, in a majority of the cases, it fails to deliver long term benefits to the patients. Therefore, there is a dire need for the discovery of a targeted therapy against this deadly breast cancer subtype.

The current study discovers one of the therapeutic vulnerabilities of TNBC which is the functional hyperactivation of epigenetic modulator EZH2 that regulates TNBC spread from breast to liver and spleen. Therefore, inhibition of EZH2 function by FDA approved EZH2 inhibitor drug Tazemetostat (EPZ6438) could be a viable option to tackle TNBC metastasis in the clinic.

Findings of the study

The study has brought into limelight that TNBC spread, particularly from breast to liver and spleen is markedly regulated by functional hyperactivation of an epigenetic modulator EZH2 (Enhancer of zeste homolog 2). This EZH2 gene codes an enzyme, which participates in histone methylation resulting in chromatin condensation and transcriptional repression of other genes. We show  that EZH2 functional overexpression or histone trimethylation (H3K27me3) is robustly and selectively increased in case of human TNBC peritoneal metastasis. Surprisingly, instead of classical H3K27me3 mediated transcriptional repression, here, we discovered, it increases KRT14 or cytokeratin-14 gene expression that turns out to be one of the critical regulators of H3K27me3 mediated TNBC peritoneal metastasis. Further, we put forward conclusive evidence that genetic loss of EZH2 or inhibition of enzymatic function of EZH2 (H3K27me3 mark) in tumor cells by inhibitors like the FDA approved drug Tazemetostat is effective in animal models to prevent TNBC peritoneal metastasis.

Decoding the methodology

The major study findings are based on preclinical animal models of TNBC where researchers determine spread of tumors cells from primary tumor site to the distant secondary organs by using live animal imaging. Overall, cutting edge and state-of-the-art biological techniques are used to draw the conclusions of the paper.

Recommendations based the study

Understanding therapeutic vulnerabilities of TNBC and development of new targeted therapies against TNBC is the need of the hour considering its high Indian prevalence. Our study suggests a strong rationale for the development of EZH2 inhibitors as potential drug candidates to prevent metastasis in patients with TNBC. It also reiterates strongly that we need to find more ways to manage this deadly disease as the TNBC burden is rising in India as well as globally.