Retinoic Acid Inhibition of Cell Cycle Progression in MCF-7 Human Breast Cancer Cells

Zhu, Wei; Jones, Carol S.; Kiss, András; Matsukuma, Karen; Amin, Sonal; Luca, Luigi M. De

doi:10.1006/excr.1997.3589

Cited by 86 publications

(60 citation statements)

References 31 publications

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“…Since cdk 2 is the partner for cyclin E, it is likely that the RA-dependent increase in p27 results in increased binding of the cyclin E/cdk 2 complex by p27, leading to decreased cyclin E/cdk 2 kinase activity and, as a consequence, hypophosphorylation of RB in mid to late G-1. This idea is supported by studies which suggest that p27 up-regulation could be a primary response in RA treated cells (Borriello et al, 2000;Matsuo and Thiele, 1998;Weber et al, 1999;Zancai et al, 1998;Zhu et al, 1997). Interestingly this upregulation is at the protein level but not at the mRNA level (Borriello et al, 2000;Matsuo and Thiele, 1998;Zancai et al, 1998).…”

Section: Discussionmentioning

confidence: 82%

Cell cycle genes as targets of retinoid induced ovarian tumor cell growth suppression

et al. 2001

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Section: Discussionmentioning

confidence: 82%

Cell cycle genes as targets of retinoid induced ovarian tumor cell growth suppression

et al. 2001

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“…Other investigators have argued that retinoic acid blocks cell cycle progression of human breast cancer cells (both MCF-7 and T-47D cell lines) in mid-G 1 [4,[47][48][49][50][51]. Wilcken et al [49] showed that RA treatment of T-47D cells decreased Rb phosphorylation within 16 h and that treated cells arrested in G 0 -G 1 between 16 and 24 h. In MCF-7 cells, retinoic acid-induced cell cycle arrest was attributed to decreased Cdk2 activity [48] and decreased cyclin D3/Cdk4 [51].…”

Section: Discussionmentioning

confidence: 99%

“…Wilcken et al [49] showed that RA treatment of T-47D cells decreased Rb phosphorylation within 16 h and that treated cells arrested in G 0 -G 1 between 16 and 24 h. In MCF-7 cells, retinoic acid-induced cell cycle arrest was attributed to decreased Cdk2 activity [48] and decreased cyclin D3/Cdk4 [51]. Although our data do not rule out G 1 targets for retinoids in T-47D cells, we believe the critical block occurs in early G 1 .…”

Section: Discussionmentioning

confidence: 99%

Retinoids arrest breast cancer cell proliferation: retinoic acid selectively reduces the duration of receptor tyrosine kinase signaling

Tighe

Talmage

2004

Experimental Cell Research

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Retinoic acid (RA) induces cell cycle arrest of hormone-dependent human breast cancer (HBC) cells. Previously, we demonstrated that RA-induced growth arrest of T-47D HBC cells required the activity of the RA-induced protein kinase, protein kinase Cα (PKCα) [J. Cell Physiol. 172 (1997) 306]. Here, we demonstrate that RA treatment of T-47D cells interfered with growth factor signaling to downstream, cytoplasmic and nuclear targets. RA treatment did not inhibit epidermal growth factor (EGF) receptor activation but resulted in rapid inactivation. The lack of sustained EGFR activation was associated with transient rather than sustained association of the EGFR with the Shc adaptor proteins and activation of Erk 1/2 and with compromised induction of expression of immediate early response genes. Inhibiting the activity of PKCα, a retinoic acid-induced target gene, prevented the effects of RA on cell proliferation and EGF signaling. Constitutive expression of PKCα, in the absence of RA, decreased cell proliferation and decreased EGF signaling. RA treatment increased steady-state levels of the protein tyrosine phosphatase PTP-1C and all measured effects of RA on EGF receptor function were reversed by the tyrosine phosphate inhibitor orthovanadate. These results indicate that RA-induced target genes, particularly PKCα, prevent sustained growth factor signaling, uncoupling activated receptor tyrosine kinases and nuclear targets that are required for cell cycle progression.

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“…In order to elucidate the mechanisms underlying the antiproliferative activity of HPR, we investigated the retinoblastoma protein pRb, whose phosphorylation plays a key role in the G1/S transition phase (Weinberg, 1995;Louvet et al, 1996;Wilcken et al, 1996), and whose continued hyperphosphorylation through S phase is required for the completion of DNA synthesis (Knudsen et al, 1998). The study was also prompted by the evidence that certain retinoids exhibiting growth suppression modulate the phosphorylation and functional status of pRb (Brooks et al, 1996;Wilcken et al, 1996;Zhu et al, 1997). In this study we have shown that treatment of breast cancer cells with HPR induced a marked dephosphorylation of pRb that involved the consensus residues for Cdk4 (Ser 780 and Ser 795 ) and Cdk2 (Ser 621 and Thr 821 ) relevant for the growth suppressive function of pRb (Connell-Crowley et al, 1997;Knudsen and Wang, 1997;Taya, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…This function of pRb, which rests on its ability to bind to and block the activity of E2F family of transcription factors and to recruit histone deacetylase (Harbour et al, 1999), is ®nely modulated by phosphorylation of pRb which progressively release these interactions (Knudsen and Wang, 1997;Connell-Crowley et al, 1997;Harbour et al, 1999). As the activity of certain compounds, including some retinoids, involves the pRb pathway (Brooks et al, 1996;Wilcken et al, 1996;Zhu et al, 1997;Chen et al, 1999), we sought to determine the role of pRb in the response to HPR.…”

Section: Prb Phosphorylation Status After Retinoid Treatmentmentioning

confidence: 99%

pRb and Cdk regulation by N-(4-hydroxyphenyl)retinamide

et al. 2000

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The cancer chemopreventive synthetic retinoid N-(4-hydroxyphenyl)retinamide (HPR) can inhibit the growth and induce apoptosis of tumor cells. In this study we analysed the growth suppressive e ect of HPR on human breast cancer cell lines in vitro and the role of the retinoblastoma protein (pRb) in this response. Treatment of MCF7, T47D and SKBR3 for 24 ± 48 h with 3 mM HPR, a concentration attainable in vivo, resulted in growth inhibition and marked dephosphorylation of pRb involving Ser 612 , Thr 821 , Ser 795 and Ser 780 , target residues for cyclin-dependent kinase 2 (Cdk2) the former two, and Cdk4 the latter two. Interestingly, this dephosphorylation of pRb occurred in S-G2-M phase cells, as revealed by experiments on cells fractionated by FACS according to the cell cycle phase, hence suggesting that the retinoid interferes with the regulation of pRb phosphorylation. The in vitro phosphorylation of a GST-pRb recombinant substrate by Cdk2 immunocomplexes from MCF7, T47D and SKBR3 was markedly suppressed after HPR treatment, whereas that by Cdk4 complexes was suppressed in T47D and SKBR3 but not in MCF7. The steady-state levels of Cdk2, Cdk4 and Cyclin A proteins were una ected by HPR, while those of Cyclin D1 were signi®cantly reduced in all three cell lines. Interestingly, Cyclin D1 downregulation by HPR correlated with transcriptional repression, but not with enhanced proteolysis of Cyclin D1 typically elicited by other retinoids. Collectively, our data suggest that the antiproliferative activity of HPR arises from its capacity to maintain pRb in a de-phosphorylated growthsuppressive status in S-G2/M, possibly through Cyclin D1 downregulation and inhibition of pRb-targeting Cdks.

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Retinoic Acid Inhibition of Cell Cycle Progression in MCF-7 Human Breast Cancer Cells

Cited by 86 publications

References 31 publications

Cell cycle genes as targets of retinoid induced ovarian tumor cell growth suppression

Cell cycle genes as targets of retinoid induced ovarian tumor cell growth suppression

Retinoids arrest breast cancer cell proliferation: retinoic acid selectively reduces the duration of receptor tyrosine kinase signaling

pRb and Cdk regulation by N-(4-hydroxyphenyl)retinamide

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