Sensitivity to DNA Damage Is a Common Component of Hormone-Based Strategies for Protection of the Mammary Gland

Tu, Yifan; Jerry, D. Joseph; Pazik, Brooke; Schneider, Sallie S.

doi:10.1158/1541-7786.mcr-05-0038

Cited by 13 publications

(7 citation statements)

References 32 publications

(38 reference statements)

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“…These observations are consistent with the effects of inoculating an adenoviral vector containing IRF1 directly into mouse mammary tumors [133]. While p53-dependent apoptosis occurs in the breast [134], T47D cells express mutant p53 and our data show that intact p53 is not required for the proapoptotic actions of IRF1 [65,97]. In AE sensitive breast cancer cells, inhibition of AE-induced IRF1 activity by dnIRF1 is accompanied by reduced proapoptotic activity [65].…”

Section: Seed-gene Model For Cell Signaling and The Regulation Of supporting

confidence: 86%

Gene network signaling in hormone responsiveness modifies apoptosis and autophagy in breast cancer cells

Clarke

Shajahan

Riggins

et al. 2009

The Journal of Steroid Biochemistry and Molecular Biology

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Resistance to endocrine therapies, whether de novo or acquired, remains a major limitation in the ability to cure many tumors that express detectable levels of the estrogen receptor alpha protein (ER). While several resistance phenotypes have been described, endocrine unresponsiveness in the context of therapy-induced tumor growth appears to be the most prevalent. The signaling that regulates endocrine resistant phenotypes is poorly understood but it involves a complex signaling network with a topology that includes redundant and degenerative features. To be relevant to clinical outcomes, the most pertinent features of this network are those that ultimately affect the endocrineregulated components of the cell fate and cell proliferation machineries. We show that autophagy, as supported by the endocrine regulation of monodansylcadaverine staining, increased LC3 cleavage, and reduced expression of p62/SQSTM1, plays an important role in breast cancer cells responding to endocrine therapy. We further show that the cell fate machinery includes both apoptotic and autophagic functions that are potentially regulated through integrated signaling that flows through key members of the BCL2 gene family and beclin-1 (BECN1). This signaling links cellular functions in mitochondria and endoplasmic reticulum, the latter as a consequence of induction of the unfolded protein response. We have taken a seed-gene approach to begin extracting critical nodes and edges that represent central signaling events in the endocrine regulation of apoptosis and autophagy. Three seed nodes were identified from global gene or protein expression analyses and supported by subsequent functional studies that established their abilities to affect cell fate. The seed nodes of nuclear factor kappa B (NFκB), interferon regulatory factor-1 (IRF1), and X-box binding protein-1 (XBP1) are linked by directional edges that support signal flow through a preliminary network that is grown to include key regulators of their individual function: NEMO/IKKγ, nucleophosmin and ER respectively. Signaling proceeds through BCL2 gene family members and BECN1 ultimately to regulate cell fate.1To whom requests for reprints should be addressed, at Room W405A Research Building,

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Section: Seed-gene Model For Cell Signaling and The Regulation Of supporting

confidence: 86%

Gene network signaling in hormone responsiveness modifies apoptosis and autophagy in breast cancer cells

Clarke

Shajahan

Riggins

et al. 2009

The Journal of Steroid Biochemistry and Molecular Biology

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“…The dose was chosen because it is close to the LD 50/30 dose in mice (24); the choice of the times was based on previous studies demonstrating that DNA fragmentation detectable by TUNEL develops 14–18 h after irradiation and sometimes extends up to 40 h (21, 25). Radiation induced marked DNA fragmentation in the different organs.…”

Section: Resultsmentioning

confidence: 99%

Deoxyribonuclease I is Essential for DNA Fragmentation Induced by Gamma Radiation in Mice

et al. 2009

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Gamma radiation is known to induce cell death in several organs. This damage is associated with endonuclease-mediated DNA fragmentation; however, the enzyme that produces the latter and is likely to cause cell death is unknown. To determine whether the most abundant cytotoxic endonuclease DNase I mediates γ-radiation-induced tissue injury, we used DNase I knockout mice and zinc chelate of 3,5-diisopropylsalicylic acid (Zn-DIPS), which, as we show, has DNase I inhibiting activity in vitro. The study demonstrated for the first time that inactivation or inhibition of DNase I ameliorates radiation injury to the white pulp of spleen, intestine villi and bone marrow as measured using a quantitative TUNEL assay. The spleen and intestine of DNase I knockout mice were additionally protected from radiation by Zn-DIPS, perhaps due to the broad radioprotective effect of the zinc ions. Surprisingly, the main DNase I-producing tissues such as the salivary glands, pancreas and kidney showed no effect of DNase I inactivation. Another unexpected observation was that even without irradiation, DNA fragmentation and cell death were significantly lower in the intestine of DNase I knockout mice than in wild-type mice. This points to the physiological role of DNase I in normal cell death in the intestinal epithelium. In conclusion, our results suggested that DNase I-mediated mechanism of DNA damage and subsequent tissue injury are essential in γ-radiation-induced cell death in radiosensitive organs.

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“…11 Importantly, fenretinide administration reduced bisretinoid production in the animal model of excessive lipofuscin accumulation. 11 However, independent of its activity as an antagonist of retinol binding to RBP4, fenretinide is an extremely active inducer of apoptosis in many cell types, [18][19][20][21][22] including the RPE, 23 Additionally, fenretinide is reported to stimulate formation of hemangiosarcomas in mice. 24 Moreover, fenretinide is theratogenic, 25,26 which makes its use problematic in Stargardt disease patients of childbearing age.…”

Section: Conclusion A1120 Significantly Reduces Accumulation Of Lipmentioning

confidence: 99%

A1120, a Nonretinoid RBP4 Antagonist, Inhibits Formation of Cytotoxic Bisretinoids in the Animal Model of Enhanced Retinal Lipofuscinogenesis

Dobri¹,

Qin²,

Kong³

et al. 2013

Invest. Ophthalmol. Vis. Sci.

122

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PURPOSE. Excessive accumulation of lipofuscin is associated with pathogenesis of atrophic age-related macular degeneration (AMD) and Stargardt disease. Pharmacologic inhibition of the retinol-induced interaction of retinol-binding protein 4 (RBP4) with transthyretin (TTR) in the serum may decrease the uptake of serum retinol to the retina and reduce formation of lipofuscin bisretinoids. We evaluated in vitro and in vivo properties of the new nonretinoid RBP4 antagonist, A1120.METHODS. RBP4 binding potency, ability to antagonize RBP4-TTR interaction, and compound specificity were analyzed for A1120 and for the prototypic RBP4 antagonist fenretinide. A1120 ability to inhibit RPE65-mediated isomerohydrolase activity was assessed in the RPE microsomes. The in vivo effect of A1120 administration on serum RBP4, visual cycle retinoids, lipofuscin bisretinoids, and retinal visual function was evaluated using a combination of biochemical and electrophysiologic techniques.RESULTS. In comparison to fenretinide, A1120 did not act as a RARa agonist, while exhibiting superior in vitro potency in RBP4 binding and RBP4-TTR interaction assays. A1120 did not inhibit isomerohydrolase activity in the RPE microsomes. A1120 dosing in mice induced 75% reduction in serum RBP4, which correlated with reduction in visual cycle retinoids and ocular levels of lipofuscin fluorophores. A1120 dosing did not induce changes in kinetics of dark adaptation. CONCLUSIONS. A1120 significantly reduces accumulation of lipofuscin bisretinoids in the Abca4À/À animal model. This activity correlates with reduction in serum RBP4 and visual cycle retinoids confirming the mechanism of action for A1120.In contrast to fenretinide, A1120 does not act as a RARa agonist indicating a more favorable safety profile for this nonretinoid compound. (Invest Ophthalmol Vis Sci. 2013; 54:85-95)

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Sensitivity to DNA Damage Is a Common Component of Hormone-Based Strategies for Protection of the Mammary Gland

Cited by 13 publications

References 32 publications

Gene network signaling in hormone responsiveness modifies apoptosis and autophagy in breast cancer cells

Gene network signaling in hormone responsiveness modifies apoptosis and autophagy in breast cancer cells

Deoxyribonuclease I is Essential for DNA Fragmentation Induced by Gamma Radiation in Mice

A1120, a Nonretinoid RBP4 Antagonist, Inhibits Formation of Cytotoxic Bisretinoids in the Animal Model of Enhanced Retinal Lipofuscinogenesis

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