Abstract
Trastuzumab (TZMB) is widely used as first line therapy for breast cancer (BC) patients overexpressing human epidermal growth factor receptor 2 (HER2). Despite its clinical benefits, many patients suffer from primary or secondary resistance to this drug within one year. As diverse molecular mechanisms occur contemporaneously during the resistance development, we focused on elucidating the role of heat shock protein 27 (HSP27) in TZMB-resistance, as this protein simultaneously regulates the function of diverse client molecules that are involved in the resistance mechanism. By extensively utilizing TZMB-refractory breast cancer cell lines transduced with diverse phosphovariants of HSP27, our study newly revealed that specific phosphorylation of HSP27 at S15 promoted its S78 phosphorylation and served as key mediator to promote direct interactions that increase the stability of HER2 and protein kinase B (AKT). This phosphorylation promoted nuclear translocation of HER2, enhancing the distinct nuclear function of HER2 that promoted AKT activation and cyclin D1 expression. Co-administration of TZMB and a functional inhibitor of HSP27, J2, significantly reduced the S15/78 phosphorylation of HSP27, which downregulated HER2 and its downstream signals, sensitizing TZMB-refractory cell, and JIMT1-xenograft mouse models to TZMB. Collectively, p-HSP27S15 could serve as a valuable predictive marker and also a therapeutic target for TZMB-resistance.
Highlights
Breast cancer (BC) is the most common cancer in women worldwide
To verify the prognostic impact of heat shock protein 27 (HSP27) in human epidermal growth factor receptor 2 (HER2)+ breast cancer (BC), we analyzed the survival probability of HER2+ BC patients using a dataset from Kaplan-Meier Plotter (KM plotter; http://kmplot.com/analysis) [36], and found that both relapse-free survival (Figure 1A; n = 251; HR, 1.65; 95% CI, 1–2.71; p = 0.046) and distant metastasis-free survival (Figure 1B; n = 119; HR, 2.42; 95% CI, 1.3–4.53; p = 0.0041) were significantly lower in patients highly expressing HSP27 than other patients
We focused on the role of HSP27 in TZMB-resistance, because it is a novel strategies are needed to comprehensively treat various refractory mechanisms at the well-known chaperone molecule that regulates the functions of diverse clients, and many previously same time
Summary
Breast cancer (BC) is the most common cancer in women worldwide. According to U.S BC statistics (breastcancer.org and the American Cancer Society), the incidence of invasive BC in U.S. women is about 12% (one in eight) over the whole lifetime. Even the risk of BC in U.S men is increasing continuously (1 in 883 in 2019). BC mortality can be dramatically ameliorated by early diagnosis and treatment, invasive BC is still the malignant disease with second highest death rate (after lung cancer) [1,2]. BC is divided into four subtypes by receptor status: luminal A (estrogen receptor (ER)-positive, progesterone receptor (PR)-positive, and human epidermal growth factor receptor 2 (HER2)-negative); luminal B (ER-positive and/or PR-positive, HER2-positive); HER2 overexpressing According to the analysis of a national cancer database
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
