PKCα Attenuates Jagged-1-Mediated Notch Signaling in ErbB-2-Positive Breast Cancer to Reverse Trastuzumab Resistance

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
K PandyaClodia Osipo

Abstract

Breast cancer is the second leading cause of cancer mortality among women worldwide. The major problem with current treatments is tumor resistance, recurrence, and disease progression. ErbB-2-positive breast tumors are aggressive and frequently become resistant to trastuzumab or lapatinib. We showed previously that Notch-1 is required for trastuzumab resistance in ErbB-2-positive breast cancer. Here, we sought to elucidate mechanisms by which ErbB-2 attenuates Notch signaling and how this is reversed by trastuzumab or lapatinib. The current study elucidates a novel Notch inhibitory mechanism by which PKCα downstream of ErbB-2 (i) restricts the availability of Jagged-1 at the cell surface to transactivate Notch, (ii) restricts the critical interaction between Jagged-1 and Mindbomb-1, an E3 ligase that is required for Jagged-1 ubiquitinylation and subsequent Notch activation, (iii) reverses trastuzumab resistance in vivo, and (iv) predicts better outcome in women with ErbB-2-positive breast cancer. The clinical impact of these studies is PKCα is potentially a good prognostic marker for low Notch activity and increased trastuzumab sensitivity in ErbB-2-positive breast cancer. Moreover, women with ErbB-2-positive breast tumors expr...Continue Reading

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Citations

Jan 9, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Yongfei LiYongmei Yin
Oct 3, 2020·Cells·McKenna BeLow, Clodia Osipo
Dec 10, 2020·Nature Reviews. Drug Discovery·Samarpan MajumderLucio Miele
Jun 14, 2018·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Deep ShahClodia Osipo
Dec 12, 2020·Advances in Biological Regulation·Adrian R Black, Jennifer D Black
May 4, 2021·Frontiers in Pharmacology·Yuanqi LiuChunfang Zhang
Jul 1, 2020·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Meng-Xi XiuBo-Hai Kuang
Aug 13, 2021·Frontiers in Endocrinology·Qiulin WuShengchun Liu

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