BRD3 Function at ERα Super Enhancers in Breast Cancers
Murakami et al. Page 2356
Bromodomain family proteins (BRDs) have come under scrutiny as a potential therapeutic target in a variety of cancers, owing to their central role in controlling transcription outputs. However, the roles of individual BRD family members are still underappreciated. Here, Murakami and colleagues define a precise role for BRD3 in estrogen receptor–positive (ER+) breast cancer cells. Chemical inhibition of BRD family members impaired estrogen-mediated gene expression, while depletion of individual BRD family members revealed partially overlapping roles in regulating the estrogen response. Interestingly, BRD3 specifically exerted its effects by buffering total BRD expression levels and activity when other family members were depleted, acting through a compensatory mechanism. Finally, BRD3 was enriched at ER-bound super enhancers associated with genes that were among the most potently activated by estrogen signaling. Together, these data reveal BRD3 as a critical mediator of the ER-dependent transcriptional program in ER+ breast cancers, and highlight its potential as a target to disrupt pathologic estrogen signaling at the transcription level.
Role of the Integrated Stress Response in Lung Cancer
Albert et al. Page 2343
Rapid proliferation of cancer cells induces harsh extracellular and intracellular conditions that must be mitigated for tumor cells to survive. In this study, Albert and colleagues demonstrate that lung adenocarcinomas (LUAD) of diverse molecular subtypes and disease stages commonly require expression of ATF4, the integrated stress response (ISR) master regulator, to cope with intrinsic and extrinsic stressors. Mechanistically, ATF4 expression was found to be regulated by eIF2α under conditions of amino acid stress. Inhibition of the ISR pathway had profound effects on cell proliferation and migration largely due to loss of asparagine synthetase (ASNS), a direct transcriptional target of ATF4 which coordinates adaptive translation of specific proteins in response to nutrient deprivation. Concordantly, loss of ASNS activity induced oxidative stress and cell cycle arrest. Taken together, the data reveal new mechanistic insights into the regulation of cellular stress in LUAD cells and highlight exploitable vulnerabilities that underlie the biology of this aggressive disease.
SIX1 in Endometrial Metaplasia and Carcinogenesis
Suen et al. Page 2369
Early-life exposure to environmental estrogens is a risk factor for the development of cancers, but the molecular pathways connecting exposure and carcinogenesis are poorly understood. Here, Suen and colleagues report new insights into the molecular underpinnings of endometrial cancer development following exposure to the estrogen mimic diethylstilbestrol (DES). SIX1, a known developmental regulator, was found to be required for normal differentiation of uterine epithelia. Accordingly, neonatal exposure of SIX1-knockout mice to DES resulted in accelerated development and altered morphology of endometrial cancers relative to wild-type. The absence of characteristic DES-induced cytokeratin (CK) 14+ basal cells in SIX1-knockout mice revealed a distinct pool of C14+/CK18+ cells that could serve as cancer progenitors. Taken together, the data indicate a tumor-suppressive role for SIX1 in regulating endometrial epithelial development and provide a key mechanistic link between synthetic estrogen exposure, aberrant differentiation, and cancer risk.
Metabolic Reprogramming and Chemoresistance in Breast Cancer
Sirois et al. Page 2492
Triple-negative breast cancers (TNBC) do not express the targetable driver oncogenes that define other subtypes, such as ER/PR and HER2, thus necessitating the use of cytotoxic chemotherapy as a primary mode of disease management. However, resistance to chemotherapy presents a major hurdle in achieving positive treatment outcomes in patients. Here, Sirois and colleagues demonstrate that the onset of resistance to two common chemotherapeutics, doxorubicin and paclitaxel, induced shared and recurrent genetic, morphologic, and metabolic changes in multiple clones of TNBC cells exposed to high-dose chemotherapy. These alterations were underpinned by an acquired reliance on perilipin 4 and, by extension, the accumulation and precise regulation of intracellular lipid droplets. These findings were also observed in clinical isolates from patients with newly acquired resistance to doxorubicin, thus highlighting new metabolic vulnerabilities in late-stage TNBC.