key: cord-0819729-vibx3q4k
authors: Nair, DHR-ICMR Young Scientist Madhumathy G; Prabhu, Jyothi S; TS, Sridhar
title: High expression of ACE2 in HER2 subtype of breast cancer is a marker of poor prognosis
date: 2021-01-23
journal: Cancer Treat Res Commun
DOI: 10.1016/j.ctarc.2021.100321
sha: fdd0e74b8325c7fcd66afaac0b471e52c16d6fa9
doc_id: 819729
cord_uid: vibx3q4k

BACKGROUND: ACE2 a key molecule of the Renin-Angiotensin system has been identified as the receptor for SARS-CoV-2 entry into human cells. In the context of human cancers, there is evidence that ACE2 might function as a tumor suppressor. The expression levels of ACE2 among the different subtypes of breast cancer has not been investigated. METHODS: We have examined the differential expression of ACE2 and its correlation with prognosis in breast cancer subtypes using the METABRIC (n=1898) and TCGA (n= 832) cohorts. Correlations were evaluated by Pearsons's correlation co-efficient and Kaplan-Meier analysis was used to estimate differences in disease-free survival between the ACE2 high and ACE2 low groups. RESULTS: There is minimal expression of ACE2 in the luminal classes, but significantly higher levels in the Basal-like and HER2-enriched subclasses. Metastatic biopsies of these tumor types also show enhanced expression of ACE2. High levels of ACE2 correlated with decreased disease-free survival in the HER2-enriched subtype, and it was positively correlated with EGFR expression. CONCLUSION: These observations suggest ACE2 might function as a context dependent factor driving tumor progression in breast cancer and permit new opportunities for targeted therapy.

 ACE2 has been identified as the most likely receptor for SARS-CoV-2. 2  We are reporting for the first time that ACE2 might have a role in driving 3 tumor progression. 4  ACE2 is highly expressed by the two aggressive subtypes of breast 5 cancer. 6  ACE2 levels were also able to predict poor prognosis in the HER2-7 enriched tumors. List of abbreviations used: 47 Angiotensin I (Ang I) 48 Angiotensin-converting enzyme 2 (ACE2) 49 EGFR (Epidermal Growth Factor Receptor) 50 Hazard Ratio (HR) 51 HER2-enriched (Human Epidermal Growth Factor Receptor 2-enriched) 52 Non-small cell lung cancer (NSCLC) 53 Pearsons's correlation co-efficient (pcc) 54 Receptor tyrosine kinase (RTK) 55 Renin-Angiotensin-Aldosterone system (RAAS) 56 Risk of relapse (ROR) 57 Tyrosine kinase inhibitors (TKIs) 

The COVID pandemic has catapulted angiotensin-converting enzyme 2 (ACE2) 86 into the spotlight since it has been identified as the most likely receptor for 87 SARS-CoV-2 entry into host cells (1) . ACE2 is a key player in the Renin- 88 Angiotensin-Aldosterone system (RAAS) that regulates vasoconstriction and 89 dilation. The RAAS axis starts with Renin, secreted by the renal juxtaglomerular 90 cells, that acts on angiotensinogen to release angiotensin I (Ang I). ACE is a 91 carboxypeptidase that acts on Ang I and converts it to Ang II which is the main 92 effector in the RAAS system with vasoconstrictive, pro-inflammatory and pro-93 fibrotic properties. A homologue of ACE, the ACE2 enzyme converts Ang I to 94 Ang (1-9) and Ang II to Ang (1-7) that mediate vasodilation, apoptosis and anti- secreted and membranous forms. The expression of ACE2 has been reported in 105 the nasal and oral mucosa, colon, skin, nasopharynx, lymph nodes, spleen, 106 human kidney, heart, testis, lung, liver, small intestine and brain [6, 7] . It is also 107 known to be expressed in arterial and venous endothelium and arterial smooth 108 muscles [8] . It is also known to be expressed in glucose accumulating tissues 109 like liver, β-cells and adipose tissue [9] . Through scRNA-seq data analysis, it 110 was reported that ACE2 expression is highest in pulmonary AT2 cells, 

High levels of ACE2 is prognostic in HER2-enriched samples and is positively 168 associated with EGFR expression. 169 We first examined the relative abundance of ACE2 across the PAM50 subtypes. (Table 2) . 197 Interestingly, in the HER2-enriched subtype, we also observed that ACE2 mRNA Chappell, Angiotensin metabolism in renal proximal tubules, urine, and serum of sheep: evidence for 292 ACE2-dependent processing of angiotensin II, Am J Physiol Renal Physiol 292 (2007) 

The emerging role of ACE2 in physiology and disease

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But Not ACE, Is Preferentially Localized to the Apical Surface of Polarized Kidney 285

Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding 288

-7) inhibits growth of human lung adenocarcinoma xenografts in nude mice through a 339 reduction in cyclooxygenase-2

Angiotensin-(1-7) reduces proliferation and 341 angiogenesis of human prostate cancer xenografts with a decrease in angiogenic factors and an 342 increase in sFlt-1

Angiotensin-converting 344 enzyme 2 attenuates the metastasis of non-small cell lung cancer through inhibition of epithelial-345 mesenchymal transition

ACE2 inhibits breast cancer 347 angiogenesis via suppressing the VEGFa/VEGFR2/ERK pathway

SARS-CoV-2 infection induces EMT-like 352 molecular changes, including ZEB1-mediated repression of the viral receptor ACE2, in lung cancer 353 models, bioRxiv

Angiotensin-converting enzyme 2 is a potential 356 therapeutic target for EGFR-mutant lung adenocarcinoma

A perspective on anti-EGFR therapies targeting triple-359 negative breast cancer

Angiotensin-converting enzyme inhibitors and cognitive decline in 362 older adults with hypertension: results from the Cardiovascular Health Study

P-interpretation of data; has drafted the work

S-interpretation of data; has drafted the work 393 All authors have read and approved the final manuscript