Abstract
NOTCH signaling is implicated in the development of breast cancer tumors. DLK2, a non-canonical inhibitor of NOTCH signaling, was previously shown to be involved in skin and breast cancer. In this work, we studied whether different levels of DLK2 expression influenced the breast cancer characteristics of MDA-MB-231 cells. We found that DLK2 overexpression inhibited NOTCH activation in a dose-dependent manner. Moreover, depending on the level of inhibition of NOTCH1 activation generated by different levels of DLK2 expression, cell proliferation, cell cycle dynamics, cell apoptosis, cell migration, and tumor growth in vivo were affected in opposite directions. Low levels of DLK2 expression produced a slight inhibition of NOTCH1 activation, and enhanced MDA-MB-231 cell invasion in vitro and cell proliferation both in vitro and in vivo. In contrast, MDA-MB-231 cells expressing elevated levels of DLK2 showed a strong inhibition of NOTCH1 activation, decreased cell proliferation, increased cell apoptosis, and were unable to generate tumors in vivo. In addition, DLK2 expression levels also affected some members of other cell signaling pathways implicated in cancer, such as ERK1/2 MAPK, AKT, and rpS6 kinases. Our data support an important role of DLK2 as a protein that can finely regulate NOTCH signaling and affect the tumor properties and growth dynamics of MDA-MB-231 breast cancer cells.
Highlights
In addition to its pivotal role during embryonic development and tissue homeostasis in adult life, NOTCH signaling is implicated in the development of numerous types of tumors
Sci. 2022, 23, 1554 they do express DLK2. We estimate that this property is suitable for studying the potential effects of the forced overexpression of DLK2 on triple-negative breast cancer cell growth without interfering with the expression of its homolog, DLK1
It was important to study the effects of different levels of DLK2 expression on the growth of MDA-MB-231 breast cancer cells and their tumorigenic properties, and compare them with the effects exerted by DLK1 in these cells, especially since NOTCH signaling was found to be a hallmark of triple-negative breast cancer tumors [36]
Summary
In addition to its pivotal role during embryonic development and tissue homeostasis in adult life, NOTCH signaling is implicated in the development of numerous types of tumors. It is accepted that NOTCH receptors may act both as oncogenes and as tumor suppressor proteins, depending on the cellular context [1–3]. The important role of NOTCH signaling in breast cancer development was established more than two decades ago with the discovery that the mouse Int oncogene, a truncated NOTCH4 protein corresponding to its active intracellular region (NICD4), was implicated in mammary tumors [4]. The inhibition of NOTCH signaling was shown to consistently suppress cell proliferation, invasiveness and migration, as well as the development and progression of breast tumors, which is of great importance for therapeutic targeting considerations [5]
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