Interplay between estrogen and retinoid signaling in breast cancer – Current and future perspectives

Ribeiro, Mariana P.C.; Santos, Ana Lúcia; Custódio, José B.A.

doi:10.1016/j.canlet.2014.07.009

Cited by 11 publications

(6 citation statements)

References 79 publications

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“…It is important to emphasize that even though E7 induces high genomic instability, this mouse does not develop cancer but only a moderate squamous epithelial hyperplasia in the exocervix [31]. As was mentioned previously, the K14E7 transgenic mice only develops cervical cancer when they are chronically treated for 6 months with 17b-estradiol; interestingly, it was reported in breast cancer that the estrogen receptors (ERa and ERb), which are activated by 17b-estradiol repress RARB gene transcription [47]. Based on these findings, one might suggest that in K14E7 transgenic mouse, the increase of Rarb expression induced by the E7 oncoprotein is given in the absence of estrogen before the tumor develops.…”

Section: Discussionmentioning

confidence: 89%

Human papillomavirus type 16 E7 oncoprotein upregulates the retinoic acid receptor-beta expression in cervical cancer cell lines and K14E7 transgenic mice

et al. 2015

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Persistent infection with high-risk human papillomaviruses is the main etiological factor in cervical cancer (CC). The human papillomavirus type 16 (HPV16) E7 oncoprotein alters several cellular processes, regulating the expression of many genes in order to avoid cell cycle control. Retinoic acid receptor beta (RARB) blocks cell growth, inducing differentiation and apoptosis. This tumor suppressor gene is gradually silenced in late passages of foreskin keratinocytes immortalized with HPV16 and in various tumors, including CC, mainly by epigenetic modifications. We investigated the effect of E7 oncoprotein on RARB gene expression. We found that HPV16 E7 increases RARB mRNA and RAR-beta protein expression both in vitro and in the cervix of young K14E7 transgenic mice. In E7-expressing cells, RARB overexpression is further increased in the presence of the tumor suppressor p53 (TP53) R273C mutant. This effect does not change when either C33-A or E7-expressing C33-A cell line is treated with Trichostatin A, suggesting that E7 enhances RARB expression independently of histone deacetylases inhibition. These findings indicate that RARB overexpression is part of the early molecular events induced by the E7 oncoprotein.

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Section: Discussionmentioning

confidence: 89%

Human papillomavirus type 16 E7 oncoprotein upregulates the retinoic acid receptor-beta expression in cervical cancer cell lines and K14E7 transgenic mice

et al. 2015

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“…Preclinical studies have shown that RA and its derivatives have significant anti-proliferative and pro-apoptotic effects in breast cancer. However, clinical trials in breast cancer patients have been disappointing; because of low efficacy, metabolic disorders, and drug resistance, especially in ER-negative breast cancer [ 2 ]. Metabolic disorders are key risk factors for breast cancer, and several clinical investigations have shown a significant association between metabolic syndrome and breast cancer in women [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

RA and ω-3 PUFA co-treatment activates autophagy in cancer cells

et al. 2017

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Retinoic acid (RA), is a promising therapeutic agent for the treatment of breast cancer. However, metabolic disorders and drug resistance reduce the efficacy of RA. In this study, we found that RA and ω-3 polyunsaturated fatty acids (ω-3 PUFAs) synergistically induced cell death in vitro and in vivo and autophagy activation. Moreover, RA-induced hypercholesterolemia was completely corrected by ω-3 PUFA supplementation. In addition, we demonstrated that the effects of this combination on the autophagic flux were independent of the two major canonic regulatory complexes controlling autophagic vesicle formation. The treatment activated Gαq-p38 MAPK signaling pathways, which resulted in autophagy of breast cancer cells. Knockdown of Gαq or P38 expression prevented RA and ω-3 PUFAs from inducing autophagy. Data indicated that Gαq-p38activation was mediated by the co-activation of GPR40 and RARα in lipid rafts, rather than by the activation of GPR120, RARβ, or RARγ. The results of this study suggest that hyperlipidemic drug side effects may be ameliorated by the administration of ω-3 PUFAs. Thus, the therapeutic indexes of the corresponding drugs may be increased.

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“…Whether there is a connection between the decreased expression of Nkx6-1 and the risk of cancer remains to be established. The nuclear receptors (RARB and THRB) that are known to cooperate with ESR1 signalling 73 , 74 also harbours the binding motifs for ESR1 within differential peaks, suggesting the potential role for these receptors in mediating the CD effects. In summary, our data suggest that the interplay between POU5F1, ZFP57 and ESR1 network is important for transgenerational inheritance of epigenetic changes caused by endocrine disrupting chemicals (e.g., CD).…”

Section: Discussionmentioning

confidence: 99%

Gestational exposure to chlordecone promotes transgenerational changes in the murine reproductive system of males

Gély-Pernot¹,

Hao²,

Legoff³

et al. 2018

Sci Rep

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Environmental factors can affect epigenetic events during germline reprogramming and impose distinctive transgenerational consequences onto the offspring. In this study, we examined the transgenerational effects of chlordecone (CD), an organochlorine insecticide with well-known estrogenic properties. We exposed pregnant mice to CD from embryonic day 6.5 to 15.5 and observed a reduction in spermatogonia (SG) numbers in F3, meiotic defects in spermatocytes and decrease in spermatozoa number in the first and third generation of male progeny. The RNA qRT-PCR expression analysis in F1 and transcriptomics analysis in F3 males using the whole testes revealed changes in the expression of genes associated with chromosome segregation, cell division and DNA repair. The expression of the master regulator of pluripotency, Pou5f1, decreased in foetal and increased in adult F1, but not in F3 adult testes. Analysis of histone H3K4me3 distribution revealed widespread changes in its occupancy in the genome of F1 and F3 generations. We established that 7.1% of altered epigenetic marks were conserved between F1 and F3 generations. The overlapping changes common to F1 and F3 include genes implicated in cell adhesion and transcription factor activities functions. Differential peaks observed in F1 males are significantly enriched in predicted ESR1 binding sites, some of which we confirmed to be functional. Our data demonstrate that CD-mediated impairment of reproductive functions could be transmitted to subsequent generations.

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Interplay between estrogen and retinoid signaling in breast cancer – Current and future perspectives

Cited by 11 publications

References 79 publications

Human papillomavirus type 16 E7 oncoprotein upregulates the retinoic acid receptor-beta expression in cervical cancer cell lines and K14E7 transgenic mice

Human papillomavirus type 16 E7 oncoprotein upregulates the retinoic acid receptor-beta expression in cervical cancer cell lines and K14E7 transgenic mice

RA and ω-3 PUFA co-treatment activates autophagy in cancer cells

Gestational exposure to chlordecone promotes transgenerational changes in the murine reproductive system of males

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