The novel findings of this article are that RET inhibition impacts not only on primary tumour growth of ER-positive breast cancers but also on their metastatic dissemination, and that the promotion of migration and metastasis of ER-positive breast cancer cells promoted by IL-6 and RET signalling is mediated by FAK activity (Figure 1).
The implications of this study are multiple. Inflammatory response pathways were previously reported to be regulated by GDNF-mediated RET activation. Particularly, a GDNF–RET set of genes associated with poor prognosis and endocrine therapy resistance was largely populated by interferon-related genes . Gattelli and colleagues for the first time highlight the functional interconnection between RET downstream signalling and inflammatory response in an endocrine therapy setting . Moreover, although RET has been shown to be an ER-dependent gene , this current study additionally shows that IL-6 can induce RET expression. The importance of this observation is that fulvestrant administration, which degrades ER and thereby disrupts ER signalling, would be expected to negatively impact on RET expression. Instead, Gattelli and colleagues show that fulvestrant induces cancer cells to produce IL-6, resulting in increased RET expression and thus creating a feed-forward RET–IL-6 expression loop. This novel observation needs to be considered to completely understand the role of RET in breast cancer.
To date, most of the mechanistic insights into RET have been described in the ER-positive breast cancer subset. However, an aspect that may be underevaluated in Gattelli and colleagues’ article is that the clinical information is based on a cohort of patients enriched for ER-negative tumours (52/89, 58.4%). Particularly, approximately 70% of the triple-negative breast cancers analysed show a high RET expression. This observation raises the intriguing question of whether an inflammatory regulation of RET expression (for example, via IL-6 signalling) could drive ER-independent RET expression. In addition, the tumour microenvironment may contribute to potentiate RET activation and signalling. Proinflammatory cytokines were reported previously to induce the expression of the RET ligand GDNF . In addition, cancer-associated fibroblasts mediate tumour-enhancing inflammation and produce IL-6 . Consequently, given the current report that IL-6 promotes RET expression, the role of the GDNF–RET axis may be more relevant in those cancers characterised by an inflammatory response and an activated tumour microenvironment.
The second important finding of this current article is that RET and IL-6 are also connected at a functional level. Previous reports state that RET binds to the FERM domain of FAK, an interaction that results in transactivation of both proteins , and that RET is degraded by autophagy in cancer cells with altered/reduced FAK signalling, preventing RET binding to FAK at focal adhesions . The novelty of Gattelli and colleagues’ article is that it demonstrates FAK is essential for IL-6-mediated RET-dependent cell migration. Both RET and FAK inhibition impaired IL-6-induced migration and metastatic ability of breast cancer cells, and, conversely, when FAK is inhibited, RET-induced and IL-6-induced migration is abolished.
These findings together have the intriguing therapeutic possibility of targeting FAK as a key signalling pathway downstream of RET to block tumour growth and metastatic potential not only in ER-positive breast cancers but also, potentially, in other breast cancer subtypes. This hypothesis may be an important strategy in tumours where an inflammatory response could increase the expression of the molecular players involved in RET–IL-6 crosstalk.