High Expression of p62 and ALDH1A3 Is Associated With Poor Prognosis in Luminal B Breast Cancer

Abstract

Background/Aim: p62 (also known as sequestosome 1) is involved in cancer progression, and high expression of p62 indicates poor clinical outcome in several cancer types. However, the association between p62 gene expression and cancer stem cells (CSCs) in breast cancer subtypes remains unclear. Materials and Methods: In the present study, genomic datasets of primary breast cancer (The Cancer Genome Atlas, n=593; and Molecular Taxonomy of Breast Cancer International Consortium, n=2,509) were downloaded. p62 Expression was then examined in normal and breast cancer tissues derived from the same patients. Kaplan-Meier and multivariate Cox regression analyses were employed to evaluate disease-specific survival. Next, the effect on cell viability and in vitro tumor-sphere formation of p62 knockdown using targeted small interfering RNA was assessed by using cells with high activity of aldehyde dehydrogenase 1 (ALDH1 high ). Results: Patients with normal-like, luminal A or luminal B breast cancer with p62 high had poor prognosis. Furthermore, patients with p62 high ALDH1A3 high luminal B type also exhibited poor prognoses. Knockdown of p62 suppressed viability and tumor-sphere formation by ALDH1 high cells of the luminal B-type cell lines BT-474 and MDA-MB- These results suggest that p62 is essential for cancerous progression of ALDH1-positive luminal B breast CSCs, and contributes to poor prognosis of luminal B breast cancer. Conclusion: p62 is potentially a prognostic marker and therapeutic target for ALDH1-positive luminal B breast CSCs.Breast cancer has the highest prevalence among cancers of women worldwide, with 2.26 million new cases (24.5% of all cancer cases in women) and 685,000 cancer-associated mortalities (15.5% of all cancer-associated mortalities among women) annually (1). Breast cancer is classified using two parameters: Immunohistochemistry and gene-expression patterns [prediction analysis of microarray 50 (PAM50)] (2-8). Based on its PAM50, breast cancer is classified into at least six subtypes: Normal-like, luminal A, luminal B, human epidermal growth factor receptor type 2 (HER2)-enriched, claudin-low and basal-like (5, 7, 8). Among these, the luminal B type expresses estrogen receptor, and certain luminal B tumors express HER2 and highly express proliferation-related genes such as marker of proliferation Ki-67 (MKI67). In addition, the luminal B type has poorer prognosis (7,(9)(10)(11)(12)(13)(14)(15). Breast cancer treatment mainly entails surgery, radiotherapy and drug therapy, including chemotherapy, endocrine therapy and molecular targeted therapy. However, there are still numerous 3299

Luminal B Breast Cancer Coexpressingp62andALDH1A3Is Less Susceptible to Radiotherapy

“…Prognostic analyses. The Kaplan-Meier method, log-rank (Cochran-Mantel-Haenszel) test and multivariate Cox regression analyses of DSS were performed as previously described (35,(50)(51)(52)(57)(58)(59)(60)(61)(62)(63)(64). Briefly, to divide patients into groups of high and low p62 and ALDH1A3 gene expression, receiver operating characteristic curves were drawn using DSS data, and the Youden index was used as the ANTICANCER RESEARCH 44: 37-47 (2024) Cell culture.…”

“…Briefly, to divide patients into groups of high and low p62 and ALDH1A3 gene expression, receiver operating characteristic curves were drawn using DSS data, and the Youden index was used as the ANTICANCER RESEARCH 44: 37-47 (2024) Cell culture. BT-474 human luminal B breast cancer cells were obtained from the American Type Culture Collection (Manassas, VA, USA) and cultured as previously described (35) with 10% fetal bovine serum (FBS; Nichirei Biosciences Inc., Tokyo, Japan).…”

“…The cells were transfected two times, 48 and 24 h before the ALDEFLUOR assay. KD efficiency was monitored using western blotting as previously described (35,50,57,59). The following primary antibodies were used: mouse monoclonal anti-p62 (610833, 1:10,000; BD Biosciences, San Jose, CA, USA); mouse monoclonal anti-β-actin (60008-1-Ig, 1:10,000; ProteinTech Group, Inc., Rosemont, IL, USA).…”

“…We have previously reported that p62 (sequestosome 1) is essential for survival/proliferation and tumor formation by ALDH1-positive CSCs in luminal B breast cancer and that p62 is involved in cancer progression and contributes to the poor prognosis in p62 high ALDH1A3 high luminal B breast cancer patients (35). p62 is a multifunctional adapter protein that is involved in various physiological functions, including nuclear factor-ĸB signaling, antioxidant responses and autophagy (36)(37)(38)(39)(40)(41)(42)(43)(44).…”

ALDH1: A potential therapeutic target for cancer stem cells in solid tumors

“…ALDH1 functions primarily by regulating vitamin A oxidation, and the expression level of ALDHI has become a marker for distinguishing normal stem cells from tumor stem cells in breast tissue ( 27 , 28 ) and is significantly correlated with a poor prognosis ( 29 – 31 ). ALDH1A1 and ALDH1A3 can dramatically enhance ALDH1 activity and are associated with a poor prognosis in patients with breast cancer ( 32 ). The elimination of ALDH1A1, ALDH1A3 inhibits ALDH1 activity, increases chemosensitivity, and reverses chemoresistance in breast cancer ( 33 ).…”