Continuous chemotherapy pressure-elicited annexin-A6 (ANXA6)-containing exosome (ANXA6-exo) secretion contributes to paclitaxel (PTX) resistance in breast cancer (BC), but the molecular mechanisms are not fully elucidated. The present study managed to investigate this issue and found that ANXA6-exo promoted PTX resistance and cancer progression in BC cells in a Yes-associated protein 1 (YAP1)-dependent manner. Specifically, the parental PTX-sensitive BC (PS-BC) cells were exposed to continuous low-dose PTX to generate PTX-resistant BC (PR-BC) cells, and we found that BC stem cells tended to be enriched in the descendent PR-BC cells in contrast with the PS-BC cells. In addition, PR-BC cell-derived exosomes were featured with highly expressed ANXA6, and ANXA6-exo delivered ANXA6 to promote cell migration, growth, autophagy, and stemness in PS-BC cells. Interestingly, ANXA6-exo increased PTX resistance in PS-BC cells via inducing autophagy, and the effects of ANXA6-exo on PTX resistance in PS-BC cells were abrogated by co-treating cells with the autophagy inhibitor 3-methyladenine. Moreover, the underlying mechanisms were uncovered, and we evidenced that ANXA6-exo up-regulated YAP1 to promote Hippo pathway dysregulation, and the promoting effects of ANXA6-exo on PTX resistance and cancer aggressiveness in BC cells were abrogated by silencing YAP1. Taken together, this study firstly elucidated the underlying mechanisms by which BCSC-derived ANXA6-exo facilitated BC progression and PTX resistance, which might help to develop novel treatment strategies for BC in clinic.
Background: The discordance of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67 cell nuclear proliferation antigen status in patients with locally advanced breast cancer pre-and post-neoadjuvant chemotherapy (NAC) is quite common. This study aimed to assess the frequency of changes in receptor status after NAC in patients with invasive ductal breast cancer and the prognostic impact of such changes.
Methods:The study comprised 670 patients who were diagnosed with invasive ductal breast carcinoma and treated with both NAC and surgery from 2012-2017. Hormone receptor (HR; including ER and PR), HER2, and Ki-67 status was assessed before NAC and in residual invasive tumor cells of the surgical specimens. The prognostic impact of receptor conversions in breast cancer patients treated with NAC was evaluated in this retrospective study.Results: The conversion of ER was related to overall survival (OS; P=0.008) and disease-free survival (DFS; P=0.004). Patients whose ER status was always positive had the best prognosis, and those who were always negative had the worst prognosis. Similar results were also found for PR status, as the conversion of PR status was also related to OS (P<0.001) and DFS (P<0.001). At the same time, the conversion of Ki-67 status was related to OS (P=0.042) and DFS (P=0.037), and patients whose Ki-67 status was ≤20% persistently after NAC had the best survival among the 4 groups, while those whose Ki-67 status changed from ≤20% to >20% after NAC had the worst survival. Nevertheless, there was no statistical significance in the conversion of HER2 status. In multivariate Cox regression analyses, PR conversion and post-neoadjuvant pathological lymph node stage (ypN) were independent prognostic factors for DFS (P=0.008, <0.001) and OS (P=0.002, <0.001).Conclusions: Changes in receptor status between pre-treatment and residual disease after NAC are common. Moreover, these alterations have an impact on the survival outcome of invasive ductal breast cancer patients. Thus, receptor status should be re-evaluated routinely before and after NAC to guide individualized treatment.
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