Abstract
Resistance to Tamoxifen constitutes a major therapeutic challenge in treating hormone sensitive breast cancer. The induction of autophagy has been shown to be involved as one of the mechanism responsible for Tamoxifen resistance. Autophagy related gene (ATG) members are the regulators and effectors of Macroautophagy process in the cellular systems. In this study, we evaluated the prognostic significance of ATGs in Tamoxifen treated breast cancer. The "Kaplan- Meier plotter" database was utilized to analyze the relevance and significance of ATGs mRNA expression to Relapse Free Survival in breast cancer patients. We used the data of patients who are Estrogen receptor positive and are treated with Tamoxifen. Hazard ratio and log-rank p-value were calculated using KM survival plots for various ATGs. Overexpressed ATG3, ATG 5, ATG 8B and PIK3R4 resulted in a poor prognosis. A gene signature of these ATGs predicts deteriorated RFS (p-value=8.3e-05 and HR=1.84 (1.35-2.51) and Distant Metastasis Free Survival (p value = 0.0027 and HR=2.03 (1.27-3.26). We report the distinct prognostic values of ATGs in patients of breast cancer treated with Tamoxifen. Thus, better understandings of the induction of autophagy pathway may potentially form the basis for use of autophagy inhibitors in the Tamoxifen treated breast cancer.
Highlights
Breast cancer is one of the most commonly occurring cancers and according to estimation by the American Cancer Society, it is the second leading cause of cancer related mortality among American women [1]
Based on the executor mechanism of autophagy, there are several ATG core proteins based functional groups: (1) The ATG1/ Unc-51 like autophagy activating kinase (ULK) complex consisted of ULK1 or
PIK3R4/p150/VPS15); (3) the ATG12 conjugation system consisted of ATG7, ATG10, ATG12, ATG16L1, and ATG5; (4) the microtubule-associated protein 1 light chain 3 (LC3) conjugation system consisted of ATG4, ATG7, ATG3, WIPI2, and LC3 protein family; and (5) the ATG9 trafficking system consisted of ATG2A and ATG2B, WIPI4, and the transmembrane protein ATG9A [16, 17]
Summary
Breast cancer is one of the most commonly occurring cancers and according to estimation by the American Cancer Society, it is the second leading cause of cancer related mortality among American women [1]. According to an estimation in the United States, there were 268,600 new cases of invasive breast cancer resulting in approximately 42,000 deaths in the year 2019 [2]. Treating breast cancer that has become resistant to drugs or has metastasized remains a big challenge [3]. Estrogen signaling is critical in the pathogenesis of breast cancer, as ~75% of breast cancers are positive for Estrogen Receptors (ER) [4] These patients are generally treated by antiestrogens and Tamoxifen, a first line drug that is extensively used to treat ER positive breast cancer [5]. Despite numerous breast cancer patients are benefited by Tamoxifen approximately 1/3rd of the patients acquire resistance to it and a clinical challenge [7]
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