Abstract
Triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer with higher rates of early relapse and metastasis, is frequently associated with aberrant activation of epithelial-mesenchymal transition (EMT). Nonetheless, how EMT is initiated and regulated during TNBC progression is not well understood. Here, we report that NUMB is a negative regulator of EMT in both human mammary epithelial cells and breast cancer cells. Reduced NUMB expression was significantly associated with elevated EMT in TNBC. Conversely, overexpression of NUMB strongly attenuated the EMT program and metastasis of TNBC cell lines. Interestingly, we showed that NUMB employs different molecular mechanisms to regulate EMT. In normal mammary epithelial cells and breast cancer cells expressing wild-type p53, NUMB suppressed EMT by stabilizing p53. However, in TNBC cells, loss of NUMB facilitated the EMT program by activating Notch signaling. Consistent with these findings, low NUMB expression and high Notch activity were significantly correlated with the TNBC subtype in patients. Collectively, these findings reveal novel molecular mechanisms of NUMB in the regulation of breast tumor EMT, especially in TNBC.
Highlights
Triple-negative breast cancer (TNBC) represents a subgroup of breast cancers that is negative for estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2) [1]
We report that NUMB is a negative regulator of epithelial-mesenchymal transition (EMT) in both human mammary epithelial cells and breast cancer cells
And 1F, knockdown of NUMB expression resulted in increased migratory and invasive behaviors in human mammary epithelial cells. These results show that suppression of NUMB expression induces the EMT program
Summary
Triple-negative breast cancer (TNBC) represents a subgroup of breast cancers that is negative for estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2) [1]. TNBC tends to exhibit aggressive and metastatic clinical behavior [1,2,3]. Epithelial-mesenchymal transition (EMT) is a developmental process in which epithelial cells lose polarity and acquire migratory and invasive properties to become mesenchymal cells [4]. EMT confers stem cell-like characteristics on cancer cells to facilitate tumor metastasis [5,6,7]. In TNBC, the aberrant activation of the EMT program has been implicated in the initiation of metastasis and aggressive progression [8, 9]. Inhibition of EMT may be a potential therapeutic strategy for TNBC patients
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