CD24 Expression and differential resistance to chemotherapy in triple-negative breast cancer

Abstract

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.

SOX2‐mediated upregulation of CD24 promotes adaptive resistance toward targeted therapy in melanoma

“…We suggest that the regulation of Src and STAT3 activity by SOX2 via CD24 is a novel mechanism of adaptive resistance toward BRAFis in melanoma cells. [38][39][40][41] This is in line with our data demonstrating that in melanoma cells an increased expression level of SOX2 or CD24 resulted in a higher tolerance toward BRAFis, while the depletion of SOX2 via KD showed higher sensitivity. Several studies have shown that CD24 and SOX2 are associated with a more undifferentiated and more cancer stem cell-like phenotype.…”

“…7,36,37 Both SOX2 and CD24 have also been linked to an increased therapy resistance. [38][39][40][41] This is in line with our data demonstrating that in melanoma cells an increased expression level of SOX2 or CD24 resulted in a higher tolerance toward BRAFis, while the depletion of SOX2 via KD showed higher sensitivity. Similarly, the KD of CD24 in the more drug resistant SOX2 OE cells led to a restoration of sensitivity.…”

Alterations of The Stem-Like Properties in The Breast Cancer Cell Line MDA-MB-231 Induced by Single Pulsed Doxorubicin Treatment

“…CD44 + /CD24 low/is one of the most studied breast cancer cell populations that is capable of tumour initiation and metastases, and results in adverse treatment outcomes (Sheridan et al, 2006;Deng et al, 2017). It has been shown (Deng et al, 2017) that in comparison to other triple negative breast cancer cell lines, MDA-MB-231 consists mostly of CD44 + /CD24cells with a relatively high resistance to doxorubicin and other anthracyclines. Our doxorubicin treated cultures displayed elevated transcriptional expression levels of both CD44 and especially of CD24 during the acute post-treatment period (DOX cultures), and returned to control levels during the recovery phase (DOX+1).…”

CD24 is a Potential Biomarker for Prognosis in Human Breast Carcinoma

“…Cluster of differentiation (CD) 24 is a small glycosyl phosphatidylinositol (GPI)-linked membrane glycoprotein (27)(28)(29)(30) amino acids in length) with glycosylation sites that bind P-selectin [7,8]. High expression levels of CD24 have been identified in various types of cancers-such as breast, prostate, pancreas, ovary, colorectal, and bladder cancers-and indicate poor prognosis [9][10][11][12].…”