RESUMEN
GCN1 is an evolutionarily-conserved ribosome-binding protein that mediates the amino acid starvation response as well as the ribotoxic stress response. We previously demonstrated that Gcn1 mutant mice lacking the GCN2-binding domain suffer from growth retardation and postnatal lethality via GCN2-independent mechanisms, while Gcn1-null mice die early in embryonic development. In this study, we explored the role of GCN1 in adult mice by generating tamoxifen-inducible conditional knockout (CKO) mice. Unexpectedly, the Gcn1 CKO mice showed body weight loss during tamoxifen treatment, which gradually recovered following its cessation. They also showed decreases in liver weight, hepatic glycogen and lipid contents, blood glucose and non-esterified fatty acids, and visceral white adipose tissue weight with no changes in food intake and viability. A decrease of serum VLDL suggested that hepatic lipid supply to the peripheral tissues was primarily impaired. Liver proteomic analysis revealed the downregulation of mitochondrial ß-oxidation that accompanied increases of peroxisomal ß-oxidation and aerobic glucose catabolism that maintain ATP levels. These findings show the involvement of GCN1 in hepatic lipid metabolism during tamoxifen treatment in adult mice.
Asunto(s)
Proteínas de Saccharomyces cerevisiae , Animales , Lípidos , Hígado/metabolismo , Glucógeno Hepático/metabolismo , Ratones , Ratones Noqueados , Factores de Elongación de Péptidos/metabolismo , Proteínas Serina-Treonina Quinasas , Proteómica , Proteínas de Unión al ARN/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Tamoxifeno/efectos adversos , Tamoxifeno/metabolismo , Transactivadores/metabolismo , Pérdida de PesoRESUMEN
PURPOSE: To describe a case of tamoxifen toxicity superimposed on central serous chorioretinopathy (CSCR). We review the role of estrogen and the effect of tamoxifen on ocular tissues. OBSERVATIONS: A 32-year-old Hispanic female with infiltrating ductal carcinoma of the left breast (T2N1M0, triple-positive), status post chemotherapy and bilateral mastectomy, presented with complaint of a floater and decreased central vision of the right eye (OD). Symptoms began three weeks after initiating tamoxifen and five months after the last cycle of chemotherapy and dexamethasone. Visual acuity (VA) was 20/30 OD at presentation. Clinical examination and multimodal imaging revealed subretinal fluid (SRF) and pigment epithelial detachment (PED) suggestive of CSCR. After one month of monitoring, VA improved to 20/20; there was SRF resolution, small PED, and focal ellipsoid zone (EZ) band loss. Two weeks later, after undergoing surgery and starting a topical steroid, she returned with count fingers (CF) VA and large SRF OD. Steroid cessation improved SRF after one month, but VA was unchanged. Tamoxifen was discontinued, and VA improved to 20/100 with near-complete resolution of SRF at three weeks, and significant reduction in choroidal thickness at two months. At final follow-up, VA was 20/200, and there was focal EZ band loss sub-foveally, minimal SRF, and small PED. CONCLUSIONS AND IMPORTANCE: Treatment with tamoxifen may lead to ocular toxicity and can complicate the recovery course of patients affected with CSCR. Variations in levels of the estrogen receptor-alpha (ER-α) and treatment with tamoxifen (ER-α partial agonist) may lead to loss of the protective effect of estrogen in the retinal pigment epithelial cells in premenopausal women. Furthermore, tamoxifen toxicity can lead to focal photoreceptor loss. Treatment in these cases should be coordinated together with the oncologist.
RESUMEN
AIM: To examine ocular findings of breast cancer patients using tamoxifen. METHODS: The records of 79 consecutive breast cancer patients were examined, retrospectively. Female patients who had previously been diagnosed to have breast cancer with either stage I, II, or III disease, and were older than 25 years of age were included in the study. Results of the ophthalmic examination, color discrimination, and contrast sensitivity tests were recorded. Short wavelength automated perimetry (SWAP) sensitivity values were obtained, and average sensitivity values of test points at 5°, 9°, 15°, and 21° from the fixation were calculated. RESULTS: Forty-nine of the patients had received 20 mg daily dose of tamoxifen therapy (tamoxifen group), while remaining 30 patients had not used tamoxifen (control group). Anterior and posterior segment examination revealed no pathologic findings in both groups. Two patients (5%) in the tamoxifen group had diffuse color loss, while none did in the control group (p = 0.523). Statistically significant differences were not detected between two groups when square roots of total error in color vision, red-green, and blue-yellow partial error scores were compared. Contrast sensitivity values were similar in both groups. Average mean deviation (MD) and average sensitivity values of test points at each 4° were statistically significantly lower in the tamoxifen group than the control group (p = 0.002, p = 0.001, p < 0.001 and p < 0.001 for right eye; p = 0.002, p= 0.001, p < 0.001 and p < 0.001 for left eye). Strong correlation was detected between MD, and duration (r = -0.832 and r = -0.842 for right and left eyes, respectively) and cumulative dose of tamoxifen use (r = -0.864 and r = -0.854 for right and left eyes, respectively). CONCLUSION: Clinically significant ocular toxicity is not frequently encountered in breast cancer patients, however, SWAP changes may occur early after tamoxifen utilization.