Triple-negative breast cancer (TNBC) is characterized by great metastasis and invasion capability. Our study revealed that nanomolar bisphenol A (BPA), one of the most ubiquitous endocrine disruptors, can increase wound closure and invasion of both MDA-MB-231 and BT-549 cells. BPA treatment can increase protein and mRNA expression of matrix metalloproteinase-2 (MMP-2) and MMP-9, while had no effect on the expression of vimentin (Vim) and fibronectin (FN) in TNBC cells. The expression of G-protein-coupled receptor (GPER), which has been suggested to mediate rapid oestrogenic signals, was not varied in BPA-treated MDA-MB-231 and BT-549 cells. Its inhibitor G15 also had no effect on BPA-induced MMPs expression and cell invasion. Interestingly, BPA treatment can significantly increase the mRNA and protein expressions of oestrogen-related receptor γ (ERRγ), but not ERRα or ERRβ, in both MDA-MB-231 and BT-549 cells. The knock-down of ERRγ can markedly attenuate BPA-induced expression of MMP-2 and MMP-9 in TNBC cells. BPA treatment can activate both ERK1/2 and Akt in TNBC cells. Both inhibitors of ERK1/2 (PD98059) and Akt (LY294002) can attenuate BPA-induced ERRγ expression and cell invasion of MDA-MB-231 cells. Collectively, our data revealed that BPA can increase the expression of MMPs and in vitro motility of TNBC cells via ERRγ. Both activation of ERK1/2 and Akt participated in this process. Our study suggests that more attention should be paid to the roles of xenoestrogens such as BPA in the development and progression of TNBC.

One of the major challenges in anticancer therapy is the poor penetration of anticancer drugs into tumors, especially in solid tumors, resulting in decreased therapeutic efficacy in vivo. To solve some of these problems, in this study, a dual-responsive polymeric micellar system has been developed. This system exhibits an ultrasensitive response to the change of pH value from the extracellular environment to the intracellular environment, resulting in micellar swelling in cancer cells via the proton sponge effect. Moreover, once the swelled micelles escape from the lysosomes in cancer cells, the disulfide linkages are ruptured by GSH in the cytoplasm, leading to the rapid release of the encapsulated drugs into the cellular nuclei. The antitumor activity in pancreatic tumor-bearing mice reveals that this dual-responsive drug delivery system possesses a long blood circulation time and can significantly promote cell internalization and intracellular drug release, achieving a high anticancer efficacy with fewer side effects for normal tissues.