Intrinsic apoptotic pathway activation increases response to anti-estrogens in luminal breast cancers

Abstract

Estrogen receptor-α positive (ERα+) breast cancer accounts for approximately 70–80% of the nearly 25,0000 new cases of breast cancer diagnosed in the US each year. Endocrine-targeted therapies (those that block ERα activity) serve as the first line of treatment in most cases. Despite the proven benefit of endocrine therapies, however, ERα+ breast tumors can develop resistance to endocrine therapy, causing disease progression or relapse, particularly in the metastatic setting. Anti-apoptotic Bcl-2 family proteins enhance breast tumor cell survival, often promoting resistance to targeted therapies, including endocrine therapies. Herein, we investigated whether blockade of anti-apoptotic Bcl-2 family proteins could sensitize luminal breast cancers to anti-estrogen treatment. We used long-term estrogen deprivation (LTED) of human ERα+ breast cancer cell lines, an established model of sustained treatment with and acquired resistance to aromatase inhibitors (AIs), in combination with Bcl-2/Bcl-xL inhibition (ABT-263), finding that ABT-263 induced only limited tumor cell killing in LTED-selected cells in culture and in vivo. Interestingly, expression and activity of the Bcl-2-related factor Mcl-1 was increased in LTED cells. Genetic Mcl-1 ablation induced apoptosis in LTED-selected cells, and potently increased their sensitivity to ABT-263. Increased expression and activity of Mcl-1 was similarly seen in clinical breast tumor specimens treated with AI + the selective estrogen receptor downregulator fulvestrant. Delivery of Mcl-1 siRNA loaded into polymeric nanoparticles (MCL1 si-NPs) decreased Mcl-1 expression in LTED-selected and fulvestrant-treated cells, increasing tumor cell death and blocking tumor cell growth. These findings suggest that Mcl-1 upregulation in response to anti-estrogen treatment enhances tumor cell survival, decreasing response to therapeutic treatments. Therefore, strategies blocking Mcl-1 expression or activity used in combination with endocrine therapies would enhance tumor cell death.

BH3 mimetics selectively eliminate chemotherapy-induced senescent cells and improve response in TP53 wild-type breast cancer

“…Senolytic drugs did not induce PARP cleavage in the untreated, proliferating Cal51 cells and had only a minimal effect on proliferating MDA-MB-175, consistent with no change or little change in cell number of proliferating cells treated with senolytic ( Fig. 1) and previous studies showing minimal activity of these drugs in solid tumor cell lines [44][45][46][47][48]. Treatment with appropriate senolytic drugs induced strong activation of caspase 3, as detected by immunofluorescence staining (Fig.…”

“…They include the BCL2 inhibitor , which is FDA approved for treatment of chronic lymphocytic leukemia [43], and ABT-263 (navitoclax), which inhibits BCL2, BCL-XL, and BCL-W and has activity in hematopoietic cancers [43]. Lamentably, these drugs have relatively minimal activity in solid tumors [44], including minimal or mixed responses as single agents in human breast cancer cell lines and xenografts [45][46][47][48].…”

MicroRNA-645 targets urokinase plasminogen activator and decreases the invasive growth of MDA-MB-231 triple-negative breast cancer cells

“… 1 , 2 There are three major subtypes of human breast cancer: endocrine-related/dependent breast cancer (estrogen receptor positive), 3 , 4 human epidermal growth factor receptor 2 (HER2)-positive breast cancer 5 – 7 and triple-negative breast cancer (TNBC) (estrogen receptor negative, progesterone receptor negative and HER2 negative). 8 , 9 While there are effective treatment strategies for endocrine-related/dependent breast cancer (tamoxifen and fulvestrant), 10 – 13 and antibody treatments (trastuzumab) 14 – 16 can effectively attenuate the progression of HER2-positive breast cancer, there is no effective therapeutic intervention for TNBC. Therefore, it is important to identify novel therapeutic molecular targets for TNBC treatment.…”

Haemolysin Sph2 of Leptospira interrogans induces cell apoptosis via intracellular reactive oxygen species elevation and mitochondrial membrane injury

“…In addition, caspase-8 can truncate Bid into tBid to induce caspase signalling through mitochondrial dysfunction (Huang et al, 2016). Intracellular signals can stimulate mitochondria to induce mitochondrial swelling and increase mitochondrial membrane permeability, which causes the loss of mitochondrial transmembrane potential (ΔΨm) and the release of apoptogenic factors, including cytochrome c, Smac/Diablo, and AIF, followed by the activation of caspase-9 and caspase-3 (Williams et al, 2018). Intracellular signals can stimulate mitochondria to induce mitochondrial swelling and increase mitochondrial membrane permeability, which causes the loss of mitochondrial transmembrane potential (ΔΨm) and the release of apoptogenic factors, including cytochrome c, Smac/Diablo, and AIF, followed by the activation of caspase-9 and caspase-3 (Williams et al, 2018).…”

“…Intracellular signals can stimulate mitochondria to induce mitochondrial swelling and increase mitochondrial membrane permeability, which causes the loss of mitochondrial transmembrane potential (ΔΨm) and the release of apoptogenic factors, including cytochrome c, Smac/Diablo, and AIF, followed by the activation of caspase-9 and caspase-3 (Williams et al, 2018). Moreover, recent reports showed that cellular reactive oxygen species (ROS) may mediate mitochondria-initiated apoptosis, because mitochondria are a primary target of ROS and a major endogenous source of ROS (Kim et al, 2017;Lin et al, 2016).…”