Herstatin inhibits heregulin-mediated breast cancer cell growth and overcomes tamoxifen resistance in breast cancer cells that overexpress HER-2

Jhabvala-Romero, Farida; Evans, Adam; Guo, Shuai; Denton, Michael; Clinton, Gail M.

doi:10.1038/sj.onc.1206912

Cited by 31 publications

(28 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Retention of intron 8 in the Her-2 transcript results in a sequence coding for herstatin, a Her-2 isoform containing a unique C terminus. Recombinant herstatin protein is capable of antagonizing Her-2-mediated growth in breast cancer cells, and herstatin message is down-regulated in carcinoma cells, providing a potential link between herstatin production and growth inhibition in breast cancer, yet it remains unclear whether herstatin protein is produced in vivo (15,22,23). Protein expression from intron-containing message has been described in the literature (24,25) for several protein isoforms including periaxin and sodium channel subunits.…”

Section: Discussionmentioning

confidence: 99%

Intron Retention Generates a Novel Id3 Isoform That Inhibits Vascular Lesion Formation

Forrest

Barringhaus

Perlegas

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

The expression of intron-containing messages has been shown to occur in a variety of diseases including lactic acidosis, Cowden Syndrome, and several cancers. However, it is unknown whether these intron-containing messages result in protein production in vivo. Indeed, intron-containing RNAs are typically retained in the nucleus, targeted for degradation, or are repressed translationally. Here, we show that during vascular lesion formation in rats, an alternative isoform of the helix-loop-helix transcription factor Id3 (Id3a) generated by intron retention is abundantly expressed. We demonstrate that Id3 is expressed early in lesion formation when the proliferative index of the neointima is highest and that Id3 promotes smooth muscle cell (SMC) proliferation and S-phase entry and inhibits transcription of the cell-cycle inhibitor p21 Cip1 . Using an Id3a-specific antibody developed by our laboratory, we show that Id3a protein is induced during vascular lesion formation and that Id3a expression peaks late when the proliferative index is low or declining and extensive apoptosis is observed. Furthermore, Id3a fails to promote SMC growth and S-phase entry or to inhibit p21 Cip1 promoter transactivation. In contrast, Id3a stimulates SMC apoptosis and inhibits endogenous Id3 production. Adenoviral delivery of Id3a inhibited lesion formation in balloon-injured rat carotid arteries in vivo. These data describe a novel feedback loop whereby intron retention generates an Id3 isoform that acts to limit SMC growth during vascular lesion formation, providing the first evidence that regulated intron retention can modulate a pathologic process in vivo.

show abstract

Section: Discussionmentioning

confidence: 99%

Intron Retention Generates a Novel Id3 Isoform That Inhibits Vascular Lesion Formation

Forrest

Barringhaus

Perlegas

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Herceptin (Trastuzumab Ò ), which is anti-ErbB2 monoclonal antibody, has been shown to be active as either a single agent or in combination with chemotherapy for ErbB2-positive metastatic breast cancer [10]. Moreover, it is also useful in diminishing the level of tamoxifen resistance of breast cancer [11,12]. Hence, the expression levels of the ErbB2 gene are closely related to successful chemotherapy against breast cancer.…”

Section: Introductionmentioning

confidence: 99%

ErbB2 overexpression in p53‐inactivated mammary epithelial cells

2006

View full text Add to dashboard Cite

Functional loss of p53 and ErbB2 overexpression are the frequent genetic alterations in human breast carcinomas. Here, we found that ErbB2 expression was upregulated in primary cultured mammary epithelial cells (MECs) isolated from mice with a defect in exons 5 and 6 of the p53 gene (p53 D5,6 ). The reporter gene activity in the p53 D5,6 MECs transfected with the À756 bp flanking region of the hErbB2 gene was higher than the wild type MECs. p53 inactivation selectively increased the level of AP-2a, but not AP-2b and AP-2c and a mutation of the two AP-2 binding sites completely inhibited the reporter activity.

show abstract

“…In MCF-7 cells, activation of ErbB3 by the growth factor ligand heregulin-b1 (HRG) induces ErbB2-ErbB3 heterodimerization and cellular proliferation (Jhabvala-Romero et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

HES-1 inhibits 17β-estradiol and heregulin-β1-mediated upregulation of E2F-1

et al. 2004

View full text Add to dashboard Cite

We have previously shown that expression of the transcription factor HES-1 is required for the growthinhibitory effect of all-trans retinoic acid on MCF-7 cells. In this study, we have used T47D cells with tetracyclinregulated expression of wild-type or a dominant-negative form of HES-1. Expression of HES-1 in T47D cells inhibited G 1 /S-phase transition and activation of Cdk2 elicited by estrogen. Estrogen treatment of T47D cells caused increased expression of E2F-1, and this expression was inhibited by cotreatment with all-trans retinoic acid. We show that the effect is mediated through HES-1, which directly downregulates E2F-1 expression through a CACGAG-site within the E2F-1 promoter. Furthermore, proliferation caused by heregulin-b1 treatment of T47D cells was inhibited by all-trans retinoic acid and this effect was mediated by HES-1. Interestingly, heregulin-b1-mediated upregulation of E2F-1 expression was directly inhibited by HES-1 through the same CACGAG-site as seen with estrogen-stimulated induction. In addition, we found that two important downstream target genes of estrogen and heregulin-b1 that are regulated through E2F-1, cyclin E and NPAT, were both regulated in a similar fashion by all-trans retinoic acid, and these effects were antagonized by dominant-negative HES-1. These findings establish that HES-1 inhibits both estrogen-and heregulin-b1-stimulated growth of breast cancer cells, and further suggest that growth inhibition induced in these cells by all-trans retinoic acid occurs via HES-1-mediated downregulation of E2F-1 expression.

show abstract

Herstatin inhibits heregulin-mediated breast cancer cell growth and overcomes tamoxifen resistance in breast cancer cells that overexpress HER-2

Cited by 31 publications

References 38 publications

Intron Retention Generates a Novel Id3 Isoform That Inhibits Vascular Lesion Formation

Intron Retention Generates a Novel Id3 Isoform That Inhibits Vascular Lesion Formation

ErbB2 overexpression in p53‐inactivated mammary epithelial cells

HES-1 inhibits 17β-estradiol and heregulin-β1-mediated upregulation of E2F-1

Contact Info

Product

Resources

About