Browsing by Subject "Breast Neoplasms / genetics"
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Item Distinct Roles of mTOR Targets S6K1 and S6K2 in Breast Cancer(MDPI, 2020-02-11) Sridharan, Savitha; Basu, AlakanandaThe mechanistic target of rapamycin (mTOR) is a master regulator of protein translation, metabolism, cell growth and proliferation. It forms two complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2). mTORC1 is frequently deregulated in many cancers, including breast cancer, and is an important target for cancer therapy. The immunosuppressant drug rapamycin and its analogs that inhibit mTOR are currently being evaluated for their potential as anti-cancer agents, albeit with limited efficacy. mTORC1 mediates its function via its downstream targets 40S ribosomal S6 kinases (S6K) and eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1). There are two homologs of S6K: S6K1 and S6K2. Most of the earlier studies focused on S6K1 rather than S6K2. Because of their high degree of structural homology, it was generally believed that they behave similarly. Recent studies suggest that while they may share some functions, they may also exhibit distinct or even opposite functions. Both homologs have been implicated in breast cancer, although how they contribute to breast cancer may differ. The purpose of this review article is to compare and contrast the expression, structure, regulation and function of these two S6K homologs in breast cancer.Item Regulation of Autophagy by Protein Kinase C-epsilon in Breast Cancer Cells(MDPI, 2020-06-15) Basu, AlakanandaProtein kinase C-ɛ (PKCɛ), an anti-apoptotic protein, plays critical roles in breast cancer development and progression. Although autophagy is an important survival mechanism, it is not known if PKCɛ regulates autophagy in breast cancer cells. We have shown that silencing of PKCɛ by siRNA inhibited basal and starvation-induced autophagy in T47D breast cancer cells as determined by the decrease in LC3-II, increase in p62, and decrease in autophagy puncta both in the presence and absence of bafilomycin A1. The mechanistic target of rapamycin (mTOR) associates with Raptor or Rictor to form complex-1 (mTORC1) or complex-2 (mTORC2), respectively. Knockdown of PKCɛ attenuated an increase in autophagy caused by the depletion of Raptor and Rictor. Overexpression of PKCɛ in MCF-7 cells caused activation of mTORC1 and an increase in LC3-I, LC3-II, and p62. The mTORC1 inhibitor rapamycin abolished the increase in LC3-I and p62. Knockdown of mTOR and Rictor or starvation enhanced autophagy in PKCɛ overexpressing cells. While overexpression of PKCɛ in MCF-7 cells inhibited apoptosis, it induced autophagy in response to tumor necrosis factor-ɑ. However, inhibition of autophagy by Atg5 knockdown restored apoptosis in PKCɛ-overexpressing cells. Thus, PKCɛ promotes breast cancer cell survival not only by inhibiting apoptosis but also by inducing autophagy.