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

Abstract

Triple-negative breast cancer (TNBC) represents an aggressive cancer subtype characterized by the lack of expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). The independence of TNBC from these growth promoting factors eliminates the efficacy of therapies which specifically target them, and limits TNBC patients to traditional systemic neo/ adjuvant chemotherapy. To better understand the growth advantage of TNBC -in the absence of ER, PR and HER2, we focused on the embryonic morphogen Nodal (associated with the cancer stem cell phenotype), which is re-expressed in aggressive breast cancers. Most notably, our previous data demonstrated that inhibition of Nodal signaling in breast cancer cells reduces their tumorigenic capacity. Furthermore, inhibiting Nodal in other cancers has resulted in improved effects of chemotherapy, although the mechanisms for this remain unknown. Thus, we hypothesized that targeting Nodal in TNBC cells in combination with conventional chemotherapy may improve efficacy and represent a potential new strategy. Our preliminary data demonstrate that Nodal is highly expressed in TNBC when compared to invasive hormone receptor positive samples. Treatment of Nodal expressing TNBC cell lines with a neutralizing anti-Nodal antibody reduces the viability of cells that had previously survived treatment with the anthracycline doxorubicin. We show that inhibiting Nodal may alter response mechanisms employed by cancer cells undergoing DNA damage. These data suggest that development of therapies which target Nodal in TNBC may lead to additional treatment options in conjunction with chemotherapy regimens -by altering signaling pathways critical to cellular survival.

Targeting the Stem Cell Properties of Adult Breast Cancer Cells: Using Combinatorial Strategies to Overcome Drug Resistance

“…From a clinical perspective, TNBC is considered a challenging disease to manage with few established targeted protocols to deploy [37–39]. Recent findings from our laboratory have revealed that Nodal protein is highly expressed in TNBC when compared directly with hormone receptor(s) (HR) and HER2 positive invasive breast cancer [9••]. A previous study of Nodal localization in 431 therapeutically naïve patients diagnosed with benign or malignant disease suggested a potential role for Nodal as a new prognostic and predictive biomarker for disease progression when compared with currently used reference markers [7••].…”

“…However, sequential treatment of these models with DOX, followed by anti-Nodal antibody therapy, resulted in significant decreases in cellular growth and viability [9]. Additional analyses revealed that inhibition of Nodal following DOX resulted in an increase in early and/or late stage apoptosis when compared to DOX or anti-Nodal treatments alone.…”

“…Nodal is a promising prognostic and predictive biomarker in breast cancer, as well as a target for therapeutic intervention [7••, 8•, 9••]. These findings may help inform the development of combinatorial approaches to target CSC subpopulations in aggressive cancers, such as TNBC.…”

LADON, a natural antisense transcript ofNODAL, promotes an invasive behaviour in melanoma cells

“…It is also expressed in the adult, notably in tissues that undergo periodical renewal or remodeling under the control of hormonal stimuli, such as the endometrium and the mammary gland (Bianco et al 2002;Papageorgiou et al 2009). Its expression in tumor cells has been correlated with the plasticity and invasive behavior of these cells (Bodenstine et al 2016;Quail et al 2013), a credible echo of its functions in embryonic and adult tissues.…”

Targeting the untargetable? Nodal expression in TNBC

“…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.…”