Abstract
Triple Negative Breast Cancer (TNBC) is a subtype of breast cancer with poor prognosis for which no targeted therapies are currently available. Notch signaling has been implicated in breast cancer but the factors that control Notch in TNBC are unknown. Because the Vacuolar ATPase has been shown to be important in breast cancer invasiveness, we investigated the role of a2-subunit isoform of Vacuolar ATPase (a2V) in regulating Notch signaling in TNBC. Confocal microscopy revealed that among all the 'a' subunit isoforms, a2V was uniquely expressed on the plasma membrane of breast cancer cells. Both a2V and NOTCH1 were elevated in TNBC tumors tissues and cell lines. a2V knockdown by siRNA as well as V-ATPase inhibition by Bafilomycin A1 (Baf A1) in TNBC cell lines enhanced Notch signaling by increasing the expression of Notch1 intracellular Domain (N1ICD). V-ATPase inhibition blocked NICD degradation by disrupting autophagy and lysosomal acidification as demonstrated by accumulation of LC3B and diminished expression of LAMP1 respectively. Importantly, treatment with Baf A1 or anti-a2V, a novel-neutralizing antibody against a2V hindered cell migration of TNBC cells. Our findings indicate that a2V regulates Notch signaling through its role in endolysosomal acidification and emerges as a potential target for TNBC.
Highlights
Breast cancer is the most common cancer in women worldwide
We report the role of a2V in regulating Notch signaling. a2V is abundantly expressed on the plasma membrane of tumor cells, making it an attractive target for anti-cancer therapies. siRNA mediated knockdown of a2V led to an increase in Notch signaling
Because we found colocalization of a2V on plasma membrane and early endosomes, we hypothesized that www.impactjournals.com/oncotarget a2V regulates Notch signaling in Triple-Negative Breast Cancers (TNBC)
Summary
Breast cancer is the most common cancer in women worldwide. The major subtypes of breast cancer are classified based on the presence or absence of hormonal receptors Estrogen (ER), Progesterone (PR) and the Human Epidermal growth factor Receptor (Her2). 15 to 20% of all breast cancers diagnosed are of the Triple-Negative subtype [1]. Triple-Negative Breast Cancers (TNBC) are defined by the lack of expression of ER/PR and Her receptors. They are highly aggressive and are more common in younger women and in women of African heritage [2, 3]. Previous studies have highlighted the role of Notch signaling in TNBC [11, 12]. Increased expression of ‘a’ subunits has been implicated in breast cancer [21, 22]. We report the role of a2V in regulating Notch signaling. A2V is abundantly expressed on the plasma membrane of tumor cells, making it an attractive target for anti-cancer therapies. Our results show that a2V inhibition blocks autophagic degradation of Notch receptor and thereby increases Notch signaling
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