CD24 Expression and differential resistance to chemotherapy in triple-negative breast cancer
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Xinyu Deng1, Sophia Apple2,*, Hong Zhao1,3,*, Jeongyoon Song1,4,*, Minna Lee1, William Luo1, Xiancheng Wu1, Debra Chung1, Richard J. Pietras5, Helena R. Chang1
1Gonda, UCLA Breast Cancer Research Laboratory and Revlon, UCLA Breast Center, Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-7028, USA
2Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095-1732, USA
3Department of Breast Surgery, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310006, P. R. China
4Department of Surgery, East-West Medical Center, Kyung Hee University College of Medicine, Dongdaemun-gu, Seoul 02447, South Korea
5Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1678, USA
*These authors contributed equally to this work
Helena R. Chang, email: firstname.lastname@example.org
Keywords: breast cancer, CD24, drug resistance, EMT, chemotherapy
Received: August 11, 2016 Accepted: February 21, 2017 Published: March 15, 2017
Breast cancer (BC) is a leading cause of cancer-related death in women. Adjuvant systemic chemotherapies are effective in reducing risks of recurrence and have contributed to reduced BC mortality. Although targeted adjuvant treatments determined by biomarkers for endocrine and HER2-directed therapies are largely successful, predicting clinical benefit from chemotherapy is more challenging. Drug resistance is a major reason for treatment failures. Efforts are ongoing to find biomarkers to select patients most likely to benefit from chemotherapy. Importantly, cell surface biomarkers CD44+/CD24– are linked to drug resistance in some reports, yet underlying mechanisms are largely unknown. This study focused on the potential role of CD24 expression in resistance to either docetaxel or doxorubicin in part by the use of triple-negative BC (TNBC) tissue microarrays. In vitro assays were also done to assess changes in CD24 expression and differential drug susceptibility after chemotherapy. Further, mouse tumor xenograft studies were done to confirm in vitro findings. Overall, the results show that patients with CD24-positive TNBC had significantly worse overall survival and disease-free survival after taxane-based treatment. Also, in vitro cell studies show that CD44+/CD24+/high cells are more resistant to docetaxel, while CD44+/CD24–/low cells are resistant to doxorubicin. Both in vitro and in vivo studies show that cells with CD24-knockdown are more sensitive to docetaxel, while CD24-overexpressing cells are more sensitive to doxorubicin. Further, mechanistic studies indicate that Bcl-2 and TGF-βR1 signaling via ATM-NDRG2 pathways regulate CD24. Hence, CD24 may be a biomarker to select chemotherapeutics and a target to overcome TNBC drug resistance.
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