Retinoids and breast cancer: From basic studies to the clinic and back again

Garattini, Enrico; Bolis, Marco; Garattini, S.; Fratelli, Maddalena; Centritto, Floriana; Paroni, Gabriela; Giannı̀, Maurizio; Zanetti, Adriana; Pagani, A; Fisher, James N.; Zambelli, Alberto; Terao, Mineko

doi:10.1016/j.ctrv.2014.01.001

Cited by 115 publications

(95 citation statements)

References 102 publications

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“…We therefore propose that the regulation of bilateral ductal symmetry is important not only for normal mammary development, but also for reducing risk of mammary neoplasia. As the majority of mammary ductal morphogenesis occurs postnatally and retinoids are of clinical interest as preventive agents in breast oncogenesis (reviewed by Garattini et al [57]), RA pathway-mediated preservation of mammary ductal symmetry may also play an important role in reducing breast cancer susceptibility. …”

Section: Resultsmentioning

confidence: 99%

Left–right analysis of mammary gland development in retinoid X receptor-α ^+/− mice

Robichaux

Fuseler

Patel

et al. 2016

Phil. Trans. R. Soc. B

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Left–right (L–R) differences in mammographic parenchymal patterns are an early predictor of breast cancer risk; however, the basis for this asymmetry is unknown. Here, we use retinoid X receptor alpha heterozygous null (RXRα +/− ) mice to propose a developmental origin: perturbation of coordinated anterior–posterior (A–P) and L–R axial body patterning. We hypothesized that by analogy to somitogenesis—in which retinoic acid (RA) attenuation causes anterior somite pairs to develop L–R asynchronously—that RA pathway perturbation would likewise result in asymmetric mammary development. To test this, mammary glands of RXRα +/− mice were quantitatively assessed to compare left- versus right-side ductal epithelial networks. Unlike wild-type controls, half of the RXRα +/− thoracic mammary gland (TMG) pairs exhibited significant L–R asymmetry, with left-side reduction in network size. In RXRα +/− TMGs in which symmetry was maintained, networks had bilaterally increased size, with left networks showing greater variability in area and pattern. Reminiscent of posterior somites, whose bilateral symmetry is refractory to RA attenuation, inguinal mammary glands (IMGs) also had bilaterally increased network size, but no loss of symmetry. Together, these results demonstrate that mammary glands exhibit differential A–P sensitivity to RXRα heterozygosity, with ductal network symmetry markedly compromised in anterior but not posterior glands. As TMGs more closely model human breast development than IMGs, these findings raise the possibility that for some women, breast cancer risk may initiate with subtle axial patterning defects that result in L–R asymmetric growth and pattern of the mammary ductal epithelium. This article is part of the themed issue ‘Provocative questions in left–right asymmetry’.

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Section: Resultsmentioning

confidence: 99%

Left–right analysis of mammary gland development in retinoid X receptor-α ^+/− mice

Robichaux

Fuseler

Patel

et al. 2016

Phil. Trans. R. Soc. B

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“…Thus, it can be speculated that CYP26C1 exerts its oncogenic effects on cells by inactivation of the 9-cis and all-trans isomers of RA. To date, no direct proof is available; however, this hypothesis is supported by a number of published studies that have previously shown that both 9-cis RA and atRA play a role in the inhibition of cell proliferation and in the induction of apoptosis and differentiation [13,14]. Consistent with the well-documented role of RA in cell proliferation inhibition, we found that increased expression of CYP26C1 was significantly associated with higher mitotic activity, as assessed by labeling of Ki-67.…”

Section: Discussionmentioning

confidence: 99%

Elevated expression of the retinoic acid-metabolizing enzyme CYP26C1 in primary breast carcinomas

Osanai

Lee

2015

Med Mol Morphol

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Retinoic acid (RA)-metabolizing enzyme CYP26A1 has been shown to have increased expression levels in breast cancers and to effectively promote the survival of breast carcinoma cells, implying a potential oncogenic function. However, the expression of CYP26C1, another CYP26 family member, in primary breast carcinoma remains to be clarified. In the present study, we examined the expression of CYP26C1 by immunohistochemistry, using three different types of microarray, and observed strong cytoplasmic staining of CYP26C1 in 73 of the 219 (33.3 %) breast carcinomas. In contrast, CYP26C1 was not expressed in normal ductal and lobular cells in non-neoplastic tissue. Interestingly, increased expression of CYP26C1 was significantly associated with a high Ki-67 labeling index and a grade of tumor. However, CYP26C1 immunoreactivity was not associated with clinicopathological variables, including primary tumor status, lymph node involvement, distant metastasis, and tumor stage. In addition, CYP26C1 positivity was independent of the expression status of the hormone receptors and immunohistochemical surrogates for the intrinsic subtypes of breast cancer. This report is the first to demonstrate elevated expression of CYP26C1 in primary breast carcinomas. Based on the RA-catabolizing activity of CYP26C1, our data suggest that CYP26C1 expression may contribute to neoplasia in the breast.

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“…ATRA, an activated metabolite of vitamin A (Clemens et al, 2013), can influence the proliferation and differentiation of both normal and cancer cells (Chen et al, 2012a). Several researches indicated that ATRA was able to induce morphological differentiation and control cells invasion and migration of many types of tumors (Garattini et al, 2014;Hu et al, 2014b;Zhang et al, 2014a), making it the foremost inducing differentiation therapeutic agent. However, because of its instability and toxicity (Gui et al, 2011;Wang et al, 2013c), ATRA was not applied extensively in clinical except for dermatosis.…”

Section: Discussionmentioning

confidence: 99%

“…Some researches have reported that the overexpression of MLCK was occurred in many cancer cells (Kucharczak et al, 2001;Mills et al, 2011;Wang et al, 2013d). Recent researches and preliminary studies in our lab demonstrated that ATRA and its derivatives could decrease tumor cells growth and migration (Gui et al, 2011;Bengtsson et al, 2013;Wang et al, 2013a;Zhang et al, 2013b;2014a;Garattini et al, 2014;Hu et al, 2014b). In our previous studies, it was explored that ATPR might inhibit tumor cells migration by down-regulating the expression of MLCK involving p38 signaling pathway (Wang et al, 2013a), one of MAPKs pathway cascade.…”

Section: Introductionmentioning

confidence: 97%

“…Subsequently, a series of studies of ATRA on APL and solid tumors were developed at full blast. Vast researches indicated that ATRA could induce cell differentiation and inhibit invasion and migration of multiple solid tumor cells, including breast cancer, gastric carcinoma and colon cancer, and so on (Bengtsson et al, 2013;Hu et al, 2012a;2014bWang et al, 2013aZhang et al, 2013b;2014a;Garattini et al, 2014;Tang et al, 2014). But its application was largely limited because of its poor solubility and high toxicity (Gui et al, 2011;Dhar et al, 2012;Clemens et al, 2013;Wang et al, 2013a;2013b).…”

Section: Introductionmentioning

confidence: 99%

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A Novel All-trans Retinoid Acid Derivative N-(3-trifluoromethyl-phenyl)-Retinamide Inhibits Lung Adenocarcinoma A549 Cell Migration through Down-regulating Expression of Myosin Light Chain Kinase

Fan

Cheng²,

Wang³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Retinoids and breast cancer: From basic studies to the clinic and back again

Cited by 115 publications

References 102 publications

Left–right analysis of mammary gland development in retinoid X receptor-α ^+/− mice

Left–right analysis of mammary gland development in retinoid X receptor-α ^+/− mice

Elevated expression of the retinoic acid-metabolizing enzyme CYP26C1 in primary breast carcinomas

A Novel All-trans Retinoid Acid Derivative N-(3-trifluoromethyl-phenyl)-Retinamide Inhibits Lung Adenocarcinoma A549 Cell Migration through Down-regulating Expression of Myosin Light Chain Kinase

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Retinoids and breast cancer: From basic studies to the clinic and back again

Cited by 115 publications

References 102 publications

Left–right analysis of mammary gland development in retinoid X receptor-α +/− mice

Left–right analysis of mammary gland development in retinoid X receptor-α +/− mice

Elevated expression of the retinoic acid-metabolizing enzyme CYP26C1 in primary breast carcinomas

A Novel All-trans Retinoid Acid Derivative N-(3-trifluoromethyl-phenyl)-Retinamide Inhibits Lung Adenocarcinoma A549 Cell Migration through Down-regulating Expression of Myosin Light Chain Kinase

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Left–right analysis of mammary gland development in retinoid X receptor-α ^+/− mice

Left–right analysis of mammary gland development in retinoid X receptor-α ^+/− mice