Isobavachalcone sensitizes cells to E2‐induced paclitaxel resistance by down‐regulating CD44 expression in ER+ breast cancer cells

Abstract

Oestrogen receptor (ER) is expressed in approximately 60%‐70% of human breast cancer. Clinical trials and retrospective analyses have shown that ER‐positive (ER+) tumours are more tolerant to chemotherapeutic drug resistance than ER‐negative (ER−) tumours. In addition, isobavachalcone (IBC) is known as a kind of phytoestrogen with antitumour effect. However, the underlying mechanism of IBC in ER+ breast cancer needs to be elucidated further. Our in vitro experiments showed that IBC could attenuate 17β‐estradiol (E2)‐induced paclitaxel resistance and that E2 could stimulate CD44 expression in ER+ breast cancer cells but not in ER− cells. Meanwhile, E2 could promote ERα expression to render ER+ breast cancer cells resistant to paclitaxel. Furthermore, we established paclitaxel‐resistant breast cancer cell lines and determined the function of ERα in the enhancement of paclitaxel resistance via the regulation of CD44 transcription. IBC down‐regulated ERα and CD44 expression and thus inhibited tumour growth in paclitaxel‐resistant xenograft models. Overall, our data demonstrated for the first time that IBC could decrease CD44 expression level via the ERα pathway and make ER+ breast cancer cells sensitive to paclitaxel treatment.

Chalcone Derivatives: Role in Anticancer Therapy

“…IBC has also been demonstrated to inhibit cell proliferation and induce apoptosis by suppressing the AKT/glycogen synthase kinase 3β (GSK3β)/β-catenin pathway in colorectal cancer cells [ 43 ]. Additionally, IBC can inhibit estrogen receptor alpha (ERα) and decrease CD44 antigen expression, which leads to decreased paclitaxel resistance in ER+ breast cancer [ 44 ]. Studies have also reported that IBC inhibits tumor formation in mouse skin cancer [ 45 ] and induces apoptosis in neuroblastoma [ 46 ].…”

Growth inhibitory efficacy of the nutritional herb Psoralea corylifolia in a model of triple‑negative breast cancer

“…The phytochemical analysis of PC has demonstrated the presence of coumarins, flavonoids and meroterpenes (19). The phytochemical isobavachalcone present in PC has been documented to increase ER-α expression, CD44 expression and affects paclitaxel resistance in MCF-7 breast cancer cells (20). In colon carcinoma-derived HCT-116 and SW480 cells, this phytochemical has documented efficacy via the AKT/GSK-3β/β-catenin axis (21), and has also been shown to inhibit cyclin D1 and CDK-4 in HCT116, SW480, LoVo and HT29 colon carcinoma-derived cellular models (22).…”

CD44ExpressionandSexModulatetheSeverityofMurineExperimentalAutoimmune Encephalomyelitis

“…In addition to sex differences in E2 expression, there are differences in progesterone, testosterone, dehydroepiandrosterone, and androstenedione [37]. Although we have no definitive mechanism elucidating the difference in disease between CD44-KO males and females, given the multiple alternative splice variants and polymorphisms in CD44 and recent studies demonstrating interactions between CD44 and E2 responses [12,45], as well as the various signaling pathways impacted by CD44 [41] and E2 [22,51], we postulate that CD44 deficiency alters hormonal effects and profiles between males and females creating the observed sex differences in disease severity. Alternatively, the presence or absence of CD44 could impact the T cell profiles in a manner independent of E2 levels, with the presence of CD44 being dominant over the E2 level in the WT animals, in contrast to the KO mice in which its absence would permit the increased E2 levels in the KO females to dominate, compared to the lower E2 levels in the KO males.…”

“…In ovarian cancer cells, CD44 forms a complex to initiate downstream signaling that ultimately promotes transcriptional activation of ERα [12]. In cervical adenocarcinoma cells, expression of a CD44 isoform is upregulated by E2 [29] while in human breast cancer cells a phytoestrogen attenuates ERα induced CD44 expression [45]. Thus, we postulate that the absence of CD44 in the CD44-KO male population coupled with a low E2 baseline expression (0.3pg/ml) [37]compared to female mice results in a more profound change in T cell subsets (specifically Th2 and Treg), which is blunted or abrogated by the presence of higher E2 levels (2.7 pg/ml) [37] in the CD44-KO female population.…”

“…Although linkages between CD44 and E2 and E2 receptor have been documented in breast and colon cancer [5,16] there is scant evidence that the two physically or functionally interact to alter each other's behavior. There are multiple polymorphisms and complex alternative splicing in CD44 and recent studies have demonstrated interactions between CD44 and E2 responses [12,29,45], in addition to the multiple known signaling pathways impacted by CD44 [41] and E2 [22,51]. As such, it is possible that CD44 and E2, both known to affect immune responsiveness in MS and EAE, could be capable of modulating each other's immune responses differentially in males and females.…”