Targeting the untargetable? Nodal expression in TNBC

KEYWORDS:

• breast cancer
• nodal
• triple negative breast cancer
• TNBC

This article refers to:

Nodal expression in triple-negative breast cancer: Cellular effects of its inhibition following doxorubicin treatment

Triple negative breast cancer (TNBC) poses a serious threat to affected patients. TNBC grows aggressively—tumors frequently demonstrate high mitotic indexes, infiltration of adjacent tissues and metastasis to lymph nodes and vital organs. Complicating therapeutic intervention, TNBC does not express the receptors which serve as targets for anti-hormonal and anti-HER2-based treatments. Consequently, patients with TNBC have a worse prognosis than hormone- or HER2 receptor-positive subtypes.¹ While TNBC may respond to chemotherapies targeting rapidly dividing cells, unwanted effects from these drugs decrease patient quality of life and limit therapeutic efficacy. Cancer cells surviving chemotherapy seed recurrence of local and metastatic disease.

There are no known targets which allow selective treatment for TNBC. The article by Bodenstine et al.² follows accumulating evidence that the protein encoded by HTX5, known as Nodal, expression is increased in a number of human cancers,³ including TNBC.

This paper establishes several findings with great potential for future clinical application: 1) Nodal is expressed in human TNBC; 2) Nodal expression is retained after TNBC cells are treated with doxorubicin; 3) Nodal promotes cancer cell survival via a p38-dependent mechanism after genotoxic insult; and, 4) Inhibition of Nodal signaling compliments conventional chemotherapy by inducing apoptosis in TNBC cells. Thus, Nodal is a potentially new therapeutic target for TNBC. Moreover, combining current therapeutic strategies with anti-Nodal therapy could provide greater efficacy at a lower dose. Such combinations would afford patients two advantages: more cancer cell killing would reduce residual disease and lower chemotherapy doses would minimize toxicity to the patient.

Although not explored directly by the authors, the Bodenstine paper poses important questions regarding how Nodal regulates the cancer stem cell (CSC) phenotype, the mechanism(s) of Nodal-mediated protection from DNA damage-induced apoptosis, and how to leverage this knowledge in designing new therapeutics to treat TNBC. Nodal is primarily known for its role in directing axis symmetry and germ layer specification during embryogenesis.⁴ However, Nodal also regulates mammary gland development,⁵ which is consistent with the data describing Nodal expression in TNBC.

Nodal directs mammary gland branching,⁵ but it remains unknown whether Nodal influences pluripotency of mammary stem cells. Is Nodal expressed in breast cancer stem cells? If Nodal maintains stemness in the mammary epithelium, then it might also influence the CSC phenotype in breast cancer. Overexpression of the Nodal receptor, Cripto-1, induces expression of markers for epithelial-to-mesenchymal transition and enhances tumorigenesis in vivo.⁶

Future studies that further reveal the biology of Nodal in human cancer could improve treatment for patients with TNBC; yet, when (pre- or post-chemotherapy?) and where (receptor, ligand, or downstream target?) to target Nodal signaling remains to be established. These data from Bodenstine et al. add to the body of research highlighting the role of developmental genes in cancer biology. Insights gleaned from development and cancer biology can reciprocally inform each other to better understand how cells in different contexts use the same set of molecular “tools” to achieve biological tasks.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.