Interfering with inflammation: a new strategy to block breast cancer self-renewal and progression?

Two recent studies show that epigenetics and inflammation play a relevant role in the regulation of transformation and cancer cell self-renewal in breast tumours, opening up the possibility that cancer progression can be controlled by interfering with inflammation cascades. Struhl's group showed that transient activation of the Src oncoprotein induces transformation and self-renewal of immortal cells via an epigenetic switch involving NF-κB, Lin28, Let-7 microRNA and IL-6. Concomitantly, Wicha's laboratory developed a strategy to selectively target cancer stem cells, retarding tumour growth and reducing metastasis by blocking the IL-8 receptor CXCR1 using either an inhibitor, repertaxin or a specific blocking antibody.


Background
Cancer development is a multistep process controlled by genetic perturbations such as activation of oncogenes or silencing of tumour suppressor genes and epigenetic events (that is, DNA methylation) occurring within a cell, as well as environmental infl uences (for instance, infl ammation) [1][2][3][4]. Th e cancer stem cell (CSC) theory implies that tumours are generated and maintained by a small population of cells with both self-renewal and diff erentiation properties that contribute to tumorigenesis and cancer cell hetero geneity. CSCs are thought to be present in several haematological and solid tumours, including breast cancer [5], and to contribute to metastasis formation and tumour recurrence after therapy. In fact, CSCs seem to be involved in the acquirement of resistance to chemo therapy, radiotherapy or targeted agents [6][7][8], and could be the main reason for treatment failures. Consequently, a relevant eff ort is required for the identifi cation of alternative treatments able to stop tumour progression and eradicate cancer.

Articles
Researchers from Struhl's group at Harvard University used the normal immortalized human mammary epithelial cell line MCF10A to evaluate the impact of a transient activation of the Src oncogene on trans formation [9]. Interestingly, they observed that this single event was able to induce an epigenetic switch leading to a permanently transformed cell line, which could form self-renewing mammospheres containing CSCs. Src activation triggered an infl ammatory response via IL-6 and created a permanent positive feedback loop involving NF-κB, Lin-28, Let-7 microRNA and STAT3.
In parallel, Ginestier and colleagues developed a strategy to target specifi cally breast CSCs by blocking the IL-8 receptor CXCR1 and therefore interfering with infl ammation [10]. Indeed, using an inhibitor for CXCR1, repertaxin or a blocking antibody, they could deplete the CSC population of two breast cancer cell lines in vitro and could target the CSCs in xenografts in mice, retarding tumour growth and reducing metastasis formation. Th ey further show that the eff ect of CXCR1 inhibition is mediated by the FAK/Akt pathway. Notably, cells presenting inactivated PTEN or overexpression of FAK are resistant to CXCR1 inhibition.

Viewpoint
Th e idea that a normal cell becomes transformed when several mutations accumulate permanently in its DNA is well accepted. Th e article by Iliopoulos and colleagues, however, reports for the fi rst time that a transient event, such as activation of Src, is suffi cient to mediate an epigenetic switch that leads to a stable transformed cell with self-renewing capacity -suggesting that not only mutations in DNA can contribute to cancer [9]. In addition, the fact that Src activation triggers an infl ammatory response opens up the possibility that targeting an infl ammatory signal at an earlier step (cytokine receptors) or at a later step (microRNA modu lation) may be suffi cient to reduce the CSC population. Th ese are major discoveries in the fi eld supported by solid experiments; owing to the important implications of these fi ndings, however, it becomes essential to transfer Struhl's approach to a mouse model of tumorigenesis.

Abstract
Two recent studies show that epigenetics and infl ammation play a relevant role in the regulation of transformation and cancer cell self-renewal in breast tumours, opening up the possibility that cancer progression can be controlled by interfering with infl ammation cascades. Struhl's group showed that transient activation of the Src oncoprotein induces transformation and self-renewal of immortal cells via an epigenetic switch involving NF-κB, Lin28, Let-7 microRNA and IL-6. Concomitantly, Wicha's laboratory developed a strategy to selectively target cancer stem cells, retarding tumour growth and reducing metastasis by blocking the IL-8 receptor CXCR1 using either an inhibitor, repertaxin or a specifi c blocking antibody. Almost as a follow-up to Iliopoulos and colleagues' work, Ginestier and coworkers prove elegantly that target ing an infl ammatory signal transduction pathway specifi c to CSCs makes reduction of tumour mass possible, overcoming the problem of chemoresistance [10]. Th e strength of this report is the fact that when using a cytotoxic agent alone, such as docetaxel, tumour mass is reduced but the CSC population is either not aff ected or is even increased. Conversely, repertaxin treatment alone or in combination with docetaxel signifi cantly reduced the number of CSCs and led to the shrinkage of tumour mass by an indirect bystander eff ect mediated by FASL/FAS signalling.
Considering that repertaxin has already been used to reduce tissue damage after myocardial infarction or stroke [11] and that clinical phase I studies demonstrate a lack of toxicity for this compound, the use of this CXCR1 inhibitor in cancer therapy seems very promising. Consequently, it is possible that a synergistic negative eff ect on CSC growth or survival can be obtained by targeting various infl ammatory signals at the same time, leading to a better outcome for several types of cancer.
In conclusion, these two articles present essential work for the breast cancer fi eld and bring together three new concepts: tumorigenesis can be initiated by one or more transient epigenetic events; tumour progression can be achieved by the activation of infl ammatory cascades; and tumour growth can be arrested or at least kept under control by blocking one or more CSC-specifi c infl ammatory stimulus.