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Persistent DNA damage foci accumulate activated DDR mediators. (A)HCA2 cells were either untreated or irradiated (10 Gy). At the indicated intervals thereafter, protein lysates were prepared. 25g were analyzed by SDS-PAGE and probed for the indicated proteins by western analysis. Membranes were exposed for different intervals to obtain optimal signals. -Actin, HSP60 and ponceaux staining (protein) were used as loading controls. (B)Cells were either untreated ('Control'), cultured to replicative senescence (SnR) or irradiated with 10 Gy and followed for 5 or 24 hours. Cells were fixed and stained for p53-pS15 (panels 1 and 3, green), total p53 (panels 4 and 6, green) or 53BP1 (panels 2 and 5, and panels 3 and 6, red). Yellow indicates merged red and green signals. (C)Earlypassage (PD25) HCA2 cells were irradiated with 10 Gy. At the indicated intervals thereafter, the irradiated cells and replicatively senescent (SnR) cells were stained as in B. Cells were scored for three or more p53 or p53-pS15 foci. Shown are the means ± s.d. from three or more independent measurements. (D)Cells were either untreated ('Control') or irradiated with 10 Gy and followed for the indicated times before being fixed and stained for 53BP1 (red) and CHK2-pT68 (green) using a rabbit antibody (Cell Signaling #2661, lot #7). Yellow indicates merged red and green signals.
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DNA damage can induce a tumor suppressive response termed cellular senescence. Damaged senescent cells permanently arrest growth, secrete inflammatory cytokines and other proteins and harbor persistent nuclear foci that contain DNA damage response (DDR) proteins. To understand how persistent damage foci differ from transient foci that mark repairab...
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... (promyelocytic leukemia protein) defines a dynamic, heterogeneous subnuclear domain (nuclear body, NB) that participates in cellular responses to stress, including genotoxic stress ( Bernardi and Pandolfi, 2007). PML NBs can be found at DNA damage foci (Carbone et al., 2002;Xu et al., 2003) and act as general sensors of genomic damage ( Varadaraj et al., 2007). Because PML also facilitates p53 activation and the senescence growth arrest (Ferbeyre et al., 2000; Pearson et al., 2000), we evaluated its relationship to damage foci during the transition to senescence after ...
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... previously showed that persistent damage foci correlate with the DDR signaling that is essential for maintaining the senescence- associated growth arrest and inflammatory cytokine secretion ( Rodier et al., 2009), consistent with our finding here that DNA- SCARS contain active CHK2 and p53 (Fig. 2). Histone H2AX is dispensable for the initial formation of DNA damage foci but is required for their stabilization ( Celeste et al., 2003). We therefore tested the idea that depletion of H2AX might disrupt DNA-SCARS and hence senescence-associated ...
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... IR (10 Gy) generated 53BP1 foci that initially showed no preferential localization to PML NBs (Fig. 3A). However, as DNA-SCARS formed, most of them associated with a PML NB. This association began ~24 hours after IR, was complete 48 hours later (Fig. 3A) and persisted for many days ( Fig. 3B; note, ~10% of control cells had damage foci, most of which were PML associated (70%), suggesting that they were DNA-SCARS or TIF in the senescent cells that are present in most normal human cell populations). Unlike 53BP1 and H2AX, which completely colocalize, PML NBs were often at the periphery of DNA-SCARS. This was true for IR-induced (Fig. 3A,B), bleomycin-induced and replicative senescence (supplementary material Fig. ...
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... many human cells, active p53 is required for both establishment and maintenance of the senescence growth arrest ( Gire and Wynford-Thomas, 1998;Rodier et al., 2009), suggesting that there is a reservoir of active p53 in senescent cells. p53 activation occurs through stabilization and posttranslational modifications, particularly Ser15 phosphorylation (p53-pS15) by DDR kinases such as ATM ( Appella and Anderson, 2001). After 10 Gy IR, HCA2 cells showed the expected rapid rise in p53 and p53-pS15 levels, followed by a decline, as detected by western analysis ( Fig. 2A). However, p53 and p53-pS15 typically declined to levels slightly above those of pre-senescent controls ( Fig. 2A). ...
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... many human cells, active p53 is required for both establishment and maintenance of the senescence growth arrest ( Gire and Wynford-Thomas, 1998;Rodier et al., 2009), suggesting that there is a reservoir of active p53 in senescent cells. p53 activation occurs through stabilization and posttranslational modifications, particularly Ser15 phosphorylation (p53-pS15) by DDR kinases such as ATM ( Appella and Anderson, 2001). After 10 Gy IR, HCA2 cells showed the expected rapid rise in p53 and p53-pS15 levels, followed by a decline, as detected by western analysis ( Fig. 2A). However, p53 and p53-pS15 typically declined to levels slightly above those of pre-senescent controls ( Fig. 2A). ...
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... on the type of cell and damage, p53 has been reported present in (Al Rashid et al., 2005) or absent ( Bakkenist and Kastan, 2003;Bekker-Jensen et al., 2006) from early DNA damage foci. We therefore asked whether p53 was present in early foci or DNA- SCARS in normal human fibroblasts. Both p53 and p53-pS15 appeared in situ at 53BP1 foci within 5 hours of 10 Gy IR; moreover, both remained associated with DNA-SCARS for at least 10 days after IR and in replicatively senescent (SnR) cells (Fig. 2B,C). The specificities of the p53 antibodies were confirmed by immunostaining bleomycin-damaged human cancer cells that were either wild-type or null for p53 (supplementary material Fig. ...
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... results demonstrate that at least a fraction of the low level of p53-pS15 detected in senescent cells by western analysis ( Fig. 2A) is contained in DNA-SCARS, suggesting that they serve as reservoirs for the p53 activity that maintains the growth ...
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... Minutes after 10 Gy IR, CHK2-pT68 staining intensity increased, but it did so throughout the nucleus and without discernible enrichment at foci (Fig. 2D). This nucleoplasmic staining generally declined within 24 hours, after which focal staining began to appear. Many hours later, CHK2-pT68 clearly localized to DNA-SCARS (Fig. 2D). The specificity of the phospho-CHK2 antibody was confirmed by immunostaining irradiated wild-type and CHK2-null cancer cells (supplementary material Fig. S1G) and using a different antibody against phospho- CHK2 (supplementary material Fig. S1H). We also detected CHK2- pT68 in the DNA-SCARS (TIF) of replicatively senescent cells (data not shown). These results reconcile earlier results (Herbig et al., 2004;Lukas et al., 2003) and suggest that, although activated CHK2 diffuses through the nucleus immediately after damage, a fraction accumulates at DNA-SCARS in senescent cells. They also suggest that TIF are selectively localized ...
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... Minutes after 10 Gy IR, CHK2-pT68 staining intensity increased, but it did so throughout the nucleus and without discernible enrichment at foci (Fig. 2D). This nucleoplasmic staining generally declined within 24 hours, after which focal staining began to appear. Many hours later, CHK2-pT68 clearly localized to DNA-SCARS (Fig. 2D). The specificity of the phospho-CHK2 antibody was confirmed by immunostaining irradiated wild-type and CHK2-null cancer cells (supplementary material Fig. S1G) and using a different antibody against phospho- CHK2 (supplementary material Fig. S1H). We also detected CHK2- pT68 in the DNA-SCARS (TIF) of replicatively senescent cells (data not shown). These results reconcile earlier results (Herbig et al., 2004;Lukas et al., 2003) and suggest that, although activated CHK2 diffuses through the nucleus immediately after damage, a fraction accumulates at DNA-SCARS in senescent cells. They also suggest that TIF are selectively localized ...
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PML-NBs, also called ND10 are matrix-bound nuclear structures that have been implicated in a variety of functions, including DNA repair, transcriptional regulation, protein degradation, and tumor suppression. These domains are also known for their potential to mediate an intracellular defense mechanism against many virus types. This is likely why t...
Citations
... [263][264][265][266][267][268][269][270] Astrocytes in AD-affected patients have been shown to display increased DNA damage and overexpress inflammatory and senescent markers such as MMP1 and IL-6. [271][272][273] Senescent astrocytes have also been reported in other NDDs, such as PD and ALS, alongside the accumulation of senescent cells at sites of pathology. [270,274] For example, Chinta et al., [274] reported a significant increase in senescent markers in the substantia nigra pars compacta of PD patients compared to agedmatched controls. ...
Neurodegenerative diseases (NDDs) affect more than 50 million people worldwide, posing a significant global health challenge as well as a high socioeconomic burden. With aging constituting one of the main risk factors for some NDDs such as Alzheimer's disease (AD) and Parkinson's disease (PD), this societal toll is expected to rise considering the predicted increase in the aging population as well as the limited progress in the development of effective therapeutics. To address the high failure rates in clinical trials, legislative changes permitting the use of alternatives to traditional pre‐clinical in vivo models are implemented. In this regard, microphysiological systems (MPS) such as organ‐on‐a‐chip (OoC) platforms constitute a promising tool, due to their ability to mimic complex and human‐specific tissue niches in vitro. This review summarizes the current progress in modeling NDDs using OoC technology and discusses five critical aspects still insufficiently addressed in OoC models to date. Taking these aspects into consideration in the future MPS will advance the modeling of NDDs in vitro and increase their translational value in the clinical setting.
... This response involves the accumulation of dysfunctional substrates within lysosomes [150]. Senescent cells secrete inflammatory cytokines and permanently arrest growth to prevent neoplastic transformation [151]. SIRTs suppress cellular senescence by inhibiting telomere attrition, stimulating DNA damage repair, and mediating inflammation [146]. ...
Ageing is an innate phenomenon that has not been fully elucidated, despite increasing research on ageing in response to the worsening global ageing population. This demographic shift leads to profound ethical and social implications for human health, delineated by the twelve hallmarks of ageing. Sirtuins, a family of NAD+ - dependent enzymes, are key in the ageing process, thus have been more extensively studied in recent years. This review summarises the mechanisms and molecular pathways through which sirtuins modulate each hallmark of ageing and therefore influence ageing and the incidence of age-related illnesses. The mounting evidence of the close interaction between sirtuins and longevity pathways indicates sirtuins’ function as therapeutic targets for extending health span and life span. We further summarise interventions which target sirtuins to modulate age-related changes on the molecular, cellular, and systemic levels.
... SnCs induced without DNA damage as by ectopic expression of p16 INK4A or p21 CIP typically do not promote inflammation, suggesting an association of the inflammatory SASP with stress responses [146]. Depleting DDR proteins like ATM, NBS1, or CHK2 [67,147], or inhibiting stress-induced p38 mitogen-activated protein kinases (MAPKs) [148], can diminish inflammatory SASP secretion. These stress signals predominantly activate NF-κB and C/EBP-β, driving the production of proinflammatory cytokines such as IL-1α, IL-6, and IL-8 [18,[149][150][151][152]. ...
Cellular senescence has recently been recognized as a hallmark of cancer, reflecting its association with aging and inflammation, its role as a response to deregulated proliferation and oncogenic stress, and its induction by cancer therapies such as radiation, chemotherapy, and targeted agents. While such therapy-induced senescence (TIS) has been linked to resistance, recurrence, metastasis and normal tissue toxicity, TIS has the potential to enhance therapy response and stimulate anti-tumor immunity. In this review, we examine the Jekyll and Hyde nature of senescent cells (SnCs), with a particular focus on how their persistence while expressing the senescence-associated secretory phenotype (SASP) modulates the tumor microenvironment through autocrine and paracrine mechanisms. Via the SASP, the formation of SnCs may alternately mediate resistance or response to conventional therapy. Further, toward fulfilling the unmet potential of cancer immunotherapy, we consider how SnCs may influence tumor inflammation and serve as a source of antigen to potentiate anti-tumor immunity. This new view suggests treatment strategies based on inducing TIS to enhance immune checkpoint blockade. Finally, we describe strategies for mitigating the detrimental effects of senescence, such as modulating the SASP or targeting SnC persistence, toward enhancing the benefits of cancer treatment.
... Sustained irreparable DSB foci have been shown to promote and maintain cellular senescence and its SASP [31,32]. Given that i-HF have been shown so far to be more sensitive to IR-induced DNA damage, we sought to determine the efficacy of DSB repair in i-HF. ...
The risk of aberrant growth of induced pluripotent stem cell (iPSC)-derived cells in response to DNA damage is a potential concern as the tumor suppressor genes TP53 and CDKN2A are transiently inactivated during reprogramming. Herein, we evaluate the integrity of cellular senescence pathways and DNA double-strand break (DSB) repair in Sendai virus reprogrammed iPSC-derived human fibroblasts (i-HF) compared to their parental skin fibroblasts (HF). Using transcriptomics analysis and a variety of functional assays, we show that the capacity of i-HF to enter senescence and repair DSB is not compromised after damage induced by ionizing radiation (IR) or the overexpression of H-RASV12. Still, i-HF lines are transcriptionally different from their parental lines, showing enhanced metabolic activity and higher expression of p53-related effector genes. As a result, i-HF lines generally exhibit increased sensitivity to various stresses, have an elevated senescence-associated secretory phenotype (SASP), and cannot be immortalized unless p53 expression is knocked down. In conclusion, while our results suggest that i-HF are not at a greater risk of transformation, their overall hyperactivation of senescence pathways may impede their function as a cell therapy product.
... 7,8 The biological effects related to RF exposure are divided into three levels: 1) interaction with biological macromolecular structures without clinical effects; 9 2) reversible morphological and functional modifications in macromolecular structures with instrumentally, clinically or subjectively demonstrable effects that quickly disappear upon cessation of the stimulus; 10 and 3) permanent biological damage that does not disappear upon cessation of the stimulus, wherein the biological effects exceed efficacy thresholds of damage repair, adaptation, and compensatory mechanisms. 11 In subjects exposed to electromagnetic fields in both urban areas and in occupational contexts, higher reactive oxygen species (ROS) production observed in neutrophils is reported to be responsible for lower levels of polymorphonuclear leukocytes. 12 The molecular changes induced by such radiation depend on a multitude of factors including the duration of radiation, tissue permeability, generation of heat, and the intensity and frequency of the waves. ...
The battle against the COVID-19 pandemic has spurred a heightened state of vigilance in global healthcare, leading to the proliferation of diverse sanitization methods. Among these approaches, germicidal lamps utilizing ultraviolet (UV) rays, particularly UV-C (wavelength ranging from 280 to 100 nm), have gained prominence for domestic use. These light-emitting diode (LED) lamps are designed to sanitize the air, objects, and surfaces. However, the prevailing concern is that these UV lamps are often introduced into the market without adequate accompanying information to ensure their safe utilization. Importantly, exposure to absorbed UV light can potentially trigger adverse biological responses, encompassing cell death and senescence. Our research encompassed a series of investigations aimed at comprehending the biological repercussions of UV-C radiation exposure from readily available domestic lamps. Our focus centered on epithelial retinal cells, keratinocytes, and fibroblasts, components of the skin and ocular targets frequently exposed to UV irradiation. Our findings underscore the potential harm associated with even brief exposure to UV, leading to irreversible and detrimental alterations in both skin cells and retinal cells of the eye. Notably, epithelial retinal cells exhibited heightened sensitivity, marked by substantial apoptosis. In contrast, keratinocytes demonstrated resilience to apoptosis even at elevated UV doses, though they were prone to senescence. Meanwhile, fibroblasts displayed a gradual amplification of both senescence and apoptosis as radiation doses escalated. In summary, despite the potential benefits offered by UV-C in deactivating pathogens like SARS-CoV-2, it remains evident that the concurrent risks posed by UV-C to human health cannot be ignored.
... Recent research on cellular senescence has revealed that senescent cells acquire an inflammatory phenotype called the senescenceassociated secretory phenotype (SASP) [17,18], which changes the surrounding microenvironment over time [19,20]. Efforts have been made to understand the phenotype of senescent cells, and cellular senescence models have been established, not only through replicative senescence [21], but also by inducing cellular senescence responses through oncogene overexpression [22], DNA damage caused by X-ray [23] or chemotherapy compounds such as doxorubicin [24]. ...
... To investigate whether UV-A radiation induces senescence in corneal endothelial cells, hCEnCs were exposed to five different doses of UV-A radiation (0 J/cm² as a mock, 2.5 J/cm², 5 J/cm², 10 J/cm², 20 J/cm²) to determine the changes in cellular morphology using phase-contrast microscopy. As a positive control, cells induced to undergo cellular senescence upon treatment with 10 Gy IR, a DNA-damaging agent, were included [23]. ...
... UV-A exposure elevates ROS production and triggers intracellular signaling pathways, whereas IR induces DNA damage response pathways through direct doublestrand breaks [23,34]. GO analysis of RNA-seq data revealed overlapping pathways that were up-or downregulated in response to UV-A and IR exposure. ...
Purpose:
The objective of this study was to investigate the senescent phenotypes of human corneal endothelial cells (hCEnCs) upon treatment with ultraviolet (UV)-A.
Methods:
We assessed cell morphology, senescence-associated β-galactosidase (SA-β-gal) activity, cell proliferation and expression of senescence markers (p16 and p21) in hCEnCs exposed to UV-A radiation, and senescent hCEnCs induced by ionizing radiation (IR) were used as positive controls. We performed RNA sequencing and proteomics analyses to compare gene and protein expression profiles between UV-A- and IR-induced senescent hCEnCs, and we also compared the results to non-senescent hCEnCs.
Results:
Cells exposed to 5 J/cm2 of UV-A or to IR exhibited typical senescent phenotypes, including enlargement, increased SA-β-gal activity, decreased cell proliferation and elevated expression of p16 and p21. RNA-Seq analysis revealed that 83.9% of the genes significantly upregulated and 82.6% of the genes significantly downregulated in UV-A-induced senescent hCEnCs overlapped with the genes regulated in IR-induced senescent hCEnCs. Proteomics also revealed that 93.8% of the proteins significantly upregulated in UV-A-induced senescent hCEnCs overlapped with those induced by IR. In proteomics analyses, senescent hCEnCs induced by UV-A exhibited elevated expression levels of several factors part of the senescence-associated secretory phenotype.
Conclusions:
In this study, where senescence was induced by UV-A, a more physiological stress for hCEnCs compared to IR, we determined that UV-A modulated the expression of many genes and proteins typically altered upon IR treatment, a more conventional method of senescence induction, even though UV-A also modulated specific pathways unrelated to IR.
... Sustained irreparable DSB foci have been shown to promote and maintain cellular senescence and its SASP [32,33]. Given that i-HF have shown so far to be more sensitive to IR-induced DNA damage, we sought to determine the efficacy of DSB repair in i-HF. ...
The risk of malignant transformation of induced pluripotent stem cells (iPSC)-derived cells in response to DNA damage is a potential concern as the tumor suppressor genes TP53 and CDKN2A are transiently inactivated during reprogramming. Here, we evaluated the integrity of cellular senescence pathways and DNA double-strand break (DSB) repair in iPSC-derived human fibroblasts (i-HF) compared to their parental skin fibroblasts (HF). Using a variety of functional assays, we show that the capacity of i-HF to enter senescence and repair DSB is not compromised after damage induced by ionizing radiation (IR) or overexpression of H-RASV12. Still, i-HF lines are transcriptionally different from their parental lines, showing enhanced metabolic activity and higher expression of p53-related effector genes. As a result, i-HF lines generally exhibit increased sensitivity to various stresses, have an elevated senescence-associated secretory phenotype (SASP) and cannot be immortalized unless p53 expression is knocked down. In conclusion, while our results suggest that i-HF are not at a greater risk of transformation, their overall hyperactivation of senescence pathways may impede their function as a cell therapy product.
... Studies have shown that factors involved in DNA repair also regulate cellular metabolism in response to DNA damage, thereby avoiding further genomic instability [35,36]. Ineffective DNA repair processes generate DNA fragments that enhance aging, which can be accelerated in cells lacking the homologous recombination repair system [37]. In summary, skeletal muscle satellite cells exhibit an elevated expression of MAPK signaling, PI3K-Akt signaling, and FoxO signaling at low passage numbers, which promote cell proliferation ability. ...
Muscle satellite cells (MuSCs) are crucial for muscle development and regeneration. The primary pig MuSCs (pMuSCs) is an ideal in vitro cell model for studying the pig’s muscle development and differentiation. However, the long-term in vitro culture of pMuSCs results in the gradual loss of their stemness, thereby limiting their application. To address this conundrum and maintain the normal function of pMuSCs during in vitro passaging, we generated an immortalized pMuSCs (SV40 T-pMuSCs) by stably expressing SV40 T-antigen (SV40 T) using a lentiviral-based vector system. The SV40 T-pMuSCs can be stably sub-cultured for over 40 generations in vitro. An evaluation of SV40 T-pMuSCs was conducted through immunofluorescence staining, quantitative real-time PCR, EdU assay, and SA-β-gal activity. Their proliferation capacity was similar to that of primary pMuSCs at passage 1, and while their differentiation potential was slightly decreased. SiRNA-mediated interference of SV40 T-antigen expression restored the differentiation capability of SV40 T-pMuSCs. Taken together, our results provide a valuable tool for studying pig skeletal muscle development and differentiation.
... Doxorubicin (Doxo) promotes severe oxidative stress and induces DNA damage, driving cells into senescence [23,34]. We evaluated the effect of Doxo treatment on erythropoiesis in Nrf2 −/− mice compared to wild-type mice. ...
Aging is characterized by increased oxidation and reduced efficiency of cytoprotective mechanisms. Nuclear factor erythroid-2-related factor (Nrf2) is a key transcription factor, controlling the expression of multiple antioxidant proteins. Here, we show that Nrf2−/− mice displayed an age-dependent anemia, due to the combined contributions of reduced red cell lifespan and ineffective erythropoiesis, suggesting a role of Nrf2 in erythroid biology during aging. Mechanistically, we found that the expression of antioxidants during aging is mediated by activation of Nrf2 function by peroxiredoxin-2. The absence of Nrf2 resulted in persistent oxidation and overactivation of adaptive systems such as the unfolded protein response (UPR) system and autophagy in Nrf2−/− mouse erythroblasts. As Nrf2 is involved in the expression of autophagy-related proteins such as autophagy-related protein (Atg) 4-5 and p62, we found impairment of late phase of autophagy in Nrf2−/− mouse erythroblasts. The overactivation of the UPR system and impaired autophagy drove apoptosis of Nrf2−/− mouse erythroblasts via caspase-3 activation. As a proof of concept for the role of oxidation, we treated Nrf2−/− mice with astaxanthin, an antioxidant, in the form of poly (lactic-co-glycolic acid) (PLGA)-loaded nanoparticles (ATS-NPs) to improve its bioavailability. ATS-NPs ameliorated the age-dependent anemia and decreased ineffective erythropoiesis in Nrf2−/− mice. In summary, we propose that Nrf2 plays a key role in limiting age-related oxidation, ensuring erythroid maturation and growth during aging.
... Additional approaches to detect SA-b-Gal expression include the flow cytometric quantification of C12FDG (5-dodecanoylaminofluorescein di-b-D-Galactopyranoside) fluorescence, a metabolite for SA-ß-Gal (142). Senescent cells are further characterized by the accumulation of reactive oxygen species (ROS) (143), an enlarged and flattened morphology, chromatin rearrangement known as senescenceassociated heterochromatic foci (SAHFs), and nuclear foci termed DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS) (144). Additional markers of senescence can include Yippee-like-3 (YPEL3) expression, a tumor suppressor that is induced by DNA damage (145,146) and downregulation of Lamin B1 expression (147). ...
Estrogen receptor positive (ER⁺) breast cancer is the most common breast cancer diagnosed annually in the US with endocrine-based therapy as standard-of-care for this breast cancer subtype. Endocrine therapy includes treatment with antiestrogens, such as selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators (SERDs), and aromatase inhibitors (AIs). Despite the appreciable remission achievable with these treatments, a substantial cohort of women will experience primary tumor recurrence, subsequent metastasis, and eventual death due to their disease. In these cases, the breast cancer cells have become resistant to endocrine therapy, with endocrine resistance identified as the major obstacle to the medical oncologist and patient. To combat the development of endocrine resistance, the treatment options for ER⁺, HER2 negative breast cancer now include CDK4/6 inhibitors used as adjuvants to antiestrogen treatment. In addition to the dysregulated activity of CDK4/6, a plethora of genetic and biochemical mechanisms have been identified that contribute to endocrine resistance. These mechanisms, which have been identified by lab-based studies utilizing appropriate cell and animal models of breast cancer, and by clinical studies in which gene expression profiles identify candidate endocrine resistance genes, are the subject of this review. In addition, we will discuss molecular targeting strategies now utilized in conjunction with endocrine therapy to combat the development of resistance or target resistant breast cancer cells. Of approaches currently being explored to improve endocrine treatment efficacy and patient outcome, two adaptive cell survival mechanisms, autophagy, and “reversible” senescence, are considered molecular targets. Autophagy and/or senescence induction have been identified in response to most antiestrogen treatments currently being used for the treatment of ER⁺ breast cancer and are often induced in response to CDK4/6 inhibitors. Unfortunately, effective strategies to target these cell survival pathways have not yet been successfully developed. Thus, there is an urgent need for the continued interrogation of autophagy and “reversible” senescence in clinically relevant breast cancer models with the long-term goal of identifying new molecular targets for improved treatment of ER⁺ breast cancer.
