Immunohistochemical Expressions of Senescence-Associated Secretory Phenotype and Its Association With Immune Microenvironments and Clinicopathological Factors in Invasive Breast Cancer

Min Hui Park,Young Kyung Bae,Jae-Ryong Kim,Jung Eun Choi

doi:10.3389/pore.2021.1609795

Min Hui Park, Young Kyung Bae + Show 2 more

Open Access

https://doi.org/10.3389/pore.2021.1609795

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Abstract

This study was undertaken to investigate immunohistochemical expression of the senescence-associated secretory phenotype (SASP) in invasive breast cancer (IBC) tissues and to determine relationships between SASP positivity and tumor microenvironments and the clinicopathological characteristics of IBC. Immunohistochemistry for senescence markers, that is, high mobility group box-1 (HMGB1), p16, p15, and decoy receptor 2 (DCR2), was performed in tissue microarrays of 1140 IBC samples. Cases positive for at least one of these four markers were considered SASP-positive. Relations between SASP and tumor characteristics, including immune microenvironments (stromal tumor-infiltrating lymphocytes [sTILs] density and numbers of intraepithelial CD103-positive [iCD103 + ] lymphocytes) and clinical outcomes were retrospectively evaluated. HMGB1, p16, p15, or DCR2 was positive in 6.7%, 26.6%, 21.1%, and 26.5%, respectively, of the 1,140 cases. Six hundred and five (53.1%) cases were SASP positive, and SASP positivity was significantly associated with histologic grade 3, high-sTIL and iCD103 + lymphocyte counts, absence of ER or PR, and a high Ki-67 index. Although SASP did not predict breast cancer-specific survival (BCSS) or disease-free survival (DFS) in the entire cohort, SASP positivity in luminal A IBC was associated with poor BCSS and DFS. However, patients with SASP-positive TNBC showed better survival than those with SASP-negative TNBC. In multivariate analysis, SASP positivity was an independent prognostic factor in both luminal A IBC and TNBC, although the effect on prognosis was the opposite. In conclusion, SASP would be involved in the modulation of immune microenvironments and tumor progression in IBC, and its prognostic significance depends on molecular subtype.

Highlights

Internal and external stimuli can damage DNA, and when this damage cannot be repaired, cells undergo aging or apoptosis
Regarding previous studies that investigated the expressions of senescence-associated markers in tumor tissues, Brezniceanu et al [26] reported that high mobility group box-1 (HMGB1) is involved in the regulation of apoptosis and that its overexpression inhibits apoptosis and promotes tumor growth
In a study on cotransfections of BAK and HMGB1 genes into NRK1 cells, Völp et al [22] revealed HMGB1 expression inhibited BAK–induced apoptosis by blocking the activities of caspase-9 and–3 and found that this anti-apoptotic effect was due to inhibitors of apoptosis proteins (IAPs) that bind to and inhibit caspases

Summary

Introduction

Internal and external stimuli can damage DNA, and when this damage cannot be repaired, cells undergo aging (senescence) or apoptosis. Senescent cells secrete inflammatory cytokines, chemokines, growth factors and matrix metalloproteinases (MMPs) and modulate their microenvironments, which is called senescence-associated secretory phenotype (SASP) and can take various cell-dependent forms [1,2,3]. Tumor cell senescence can be induced by oncogenes, radiotherapy, or chemotherapy, and senescent tumor cells that acquire SASP change tumor microenvironments. SASP factors are known to display anti-tumor effects by inducing the senescence of surrounding tumor cells through paracrine or autocrine mechanisms or by activating the host immune system to remove tumor cells [4,5,6]. Cancer cells exhibiting SASP cause chronic inflammation, tissue fibrosis, and increase tumor cell drug resistance [4]

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