Abstract
Aggressive cancer cells are characterized by their capacity to proliferate indefinitely and to propagate a heterogeneous tumor comprised of subpopulations with varying degrees of metastatic propensity and drug resistance properties. Particularly daunting is the challenge we face in the field of oncology of effectively targeting heterogeneous tumor cells expressing a variety of markers, especially those associated with a stem cell phenotype. This dilemma is especially relevant in breast cancer, where therapy is based on traditional classification schemes, including histological criteria, differentiation status, and classical receptor markers. However, not all patients respond in a similar manner to standard-of-care therapy, thereby necessitating the need to identify and evaluate novel biomarkers associated with the difficult-to-target stem cell phenotype and drug resistance. Findings related to the convergence of embryonic and tumorigenic signaling pathways have identified the embryonic morphogen Nodal as a promising new oncofetal target that is reactivated only in aggressive cancers, but not in normal tissues. The work presented in this paper confirms previous studies demonstrating the importance of Nodal as a cancer stem cell molecule associated with aggressive breast cancer, and advances the field by providing new findings showing that Nodal is not targeted by standard-of-care therapy in breast cancer patients. Most noteworthy is the linkage found between Nodal expression and the drug resistance marker ATP-binding cassette member 1 (ABCA1), which may provide new insights into developing combinatorial approaches to overcome drug resistance and disease recurrence.
Highlights
Decades’ worth of research has sought to define the various stages of breast cancer progression with the overall goal of improving the prediction of disease outcome
A previous, noteworthy breast cancer study from our laboratory focused on Nodal localization in 431 therapeutically naïve patients diagnosed with benign or malignant disease and revealed a potential role for Nodal as a new prognostic biomarker for disease progression when compared with currently used reference markers [16]
Based on the observations derived from our previous studies in melanoma patients and related animal models—where treatment with conventional dacarbazine or BRAF inhibitors did not diminish Nodal expression [14,17]—we postulated that Nodal would remain before and after standard-of-care therapy in breast cancer patients
Summary
Decades’ worth of research has sought to define the various stages of breast cancer progression with the overall goal of improving the prediction of disease outcome. The Nottingham grading system has specified key architectural features that further define invasive breast cancer and are critical to classifying the differentiation status, with a poorly differentiated phenotype being the hallmark of more aggressive disease [2]. One of the most daunting challenges we face in the oncological sciences is developing the most effective targeting of these heterogeneous tumors containing breast cancer cells expressing various markers, especially those associated with stem cells, for which targeted therapies are currently under development. Noteworthy is the phenotype associated with aggressive triple-negative breast cancer (TNBC), which exhibits little-to-no expression of classical markers, and patients are at significantly higher risk of relapsing with metastatic disease following treatment with standard-of-care therapies. There is a critical need to identify novel targetable molecules that can enhance current therapies by mitigating the stem cell phenotype of aggressive breast cancer and concurrently reversing drug resistance
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