title: CD44 expression contributes to trastuzumab resistance in HER2-positive breast cancer cells.
abstract: Resistance to HER2-targeted therapies remains a major obstacle in the treatment of HER2-overexpressing breast cancer. CD44, a putative breast cancer stem cell (CSC) marker, is overexpressed in trastuzumab-resistant breast cancer cells. While CSC-related genes may play a role in the development of trastuzumab resistance, conflicting results have been published about CSC response to trastuzumab. We hypothesized that CD44 contributes to trastuzumab resistance independently of its role as a CSC marker. We used trastuzumab-sensitive breast cancer cell lines and their trastuzumab-resistant isogenic counterparts to evaluate the role of CD44 in response to trastuzumab. miRNA and mRNA expression were analyzed using microarray chips. A gene set enrichment analysis was created and matched with response to trastuzumab in cells and patient samples. The proportions of CSC in trastuzumab-resistant cells were similar to or lower than in the trastuzumab-sensitive cells. However, CD44 expression levels were significantly higher in both trastuzumab-resistant cell lines and its knockdown led to an increased response to trastuzumab. The invasiveness and anchorage-independent growth of trastuzumab-resistant cells were higher and blocked by downregulation of CD44. Results also showed that CD44-related resistance to trastuzumab is regulated by miRNAs. We identified a CD44-related gene expression profile that correlated with response to trastuzumab in cell lines and breast cancer patients. CD44 mediates trastuzumab resistance in HER2-positive breast cancer cells independently of its role as a CSC marker and that this role of CD44 is partly regulated by miRNA.
authors.affiliation: Departments of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Delphine R
authors.initials: DR
authors.lastname: Boulbes
authors.forename: Gaurav B
authors.initials: GB
authors.lastname: Chauhan
authors.forename: Quanri
authors.initials: Q
authors.lastname: Jin
authors.forename: Chandra
authors.initials: C
authors.lastname: Bartholomeusz
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Esteva
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D000068878:Trastuzumab / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D018960:Hyaluronan Receptors; D035683:MicroRNAs; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab