Two somatic biallelic lesions within and near <i>SMAD4</i> in a human breast cancer cell line

Jakob, John; Nagase, Satoru; Gazdar, Adi F.; Chien, Minchen; Morozova, Irina; Russo, James J.; Nandula, Subhadra V.; Murty, Vundavalli V.; Li, Chi Ming; Tycko, Benjamin; Parsons, Ramon

doi:10.1002/gcc.20142

Cited by 10 publications

(8 citation statements)

References 37 publications

(37 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The high frequency of Smad4 mutations in human tumors [32-35] suggests a role for Smad4 as a tumor suppressor independent of TGF-β signaling. Smad4 mutations in breast carcinoma have also been reported [36,37]. In addition, the work on Smad4 conditional knockout mice also indicates that Smad4 is required for the suppression function of TGF-β in the proliferation of mammary epithelial cells [38].…”

Section: Discussionmentioning

confidence: 99%

Dual effects of TGF-β on ERα-mediated estrogenic transcriptional activity in breast cancer

Ren

Frost

et al. 2009

Mol Cancer

View full text Add to dashboard Cite

BackgroundTGF-β resistance often develops in breast cancer cells that in turn overproduce this cytokine to create a local immunosuppressive environment that fosters tumor growth and exacerbates the invasive and metastatic behavior of the tumor cells themselves. Smads-mediated cross-talk with the estrogen receptor has been implied to play an important role in development and/or progression of breast cancer. We investigated how TGF-β regulates ERα-induced gene transcription and potential mechanisms of frequent TGF-β resistance in breast cancer.MethodsEffect of TGF-β on ERα-mediated gene transcription was investigated in breast cancer cell lines using transient transfection, real-time PCR, sequential DNA precipitation, and small interfering RNA assays. The expression of Smads on both human breast cancer cell lines and ERα-positive human breast cancer tissue was evaluated by immunofluorescence and immunohistochemical assays.ResultsA complex of Smad3/4 mediates TGF-β inhibition of ERα-mediated estrogenic activity of gene transcription in breast cancer cells, and Smad4 is essential and sufficient for such repression. Either overexpression of Smad3 or inhibition of Smad4 leads to the "switch" of TGF-β from a repressor to an activator. Down-regulation and abnormal cellular distribution of Smad4 were associated with some ERα-positive infiltrating human breast carcinoma. There appears a dynamic change of Smad4 expression from benign breast ductal tissue to infiltrating ductal carcinoma.ConclusionThese results suggest that aberrant expression of Smad4 or disruption of Smad4 activity lead to the loss of TGF-β suppression of ERα transactivity in breast cancer cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Dual effects of TGF-β on ERα-mediated estrogenic transcriptional activity in breast cancer

Ren

Frost

et al. 2009

Mol Cancer

View full text Add to dashboard Cite

show abstract

“…Likewise, mutations in TGFBR1 are relatively rare in breast or skin cancer 18. Loss of heterozygosity (LOH) on chromosome 18q, that harbors SMAD4, is seen in 30% of breast tumors, but specific SMAD4 mutations within this large region of LOH are only seen in 12% of tumors 21. On the other hand, LOH at either SMAD2 and/or SMAD4, which are closely linked on human chromosome 18q, was reported in the majority of 17 human skin squamous cell carcinoma (SCC) specimens examined.…”

Section: The Role Of Tgf-β Signaling In Tumorigenesis and Progressionmentioning

confidence: 99%

Complexities of TGF-β Targeted Cancer Therapy

Connolly¹,

Freimuth²,

Akhurst³

2012

Int. J. Biol. Sci.

311

300

View full text Add to dashboard Cite

Many advanced tumors produce excessive amounts of Transforming Growth Factor-β (TGF-β) which, in normal epithelial cells, is a potent growth inhibitor. However, in oncogenically activated cells, the homeostatic action of TGF-β is often diverted along alternative pathways. Hence, TGF-β signaling elicits protective or tumor suppressive effects during the early growth-sensitive stages of tumorigenesis. However, later in tumor development when carcinoma cells become refractory to TGF-β-mediated growth inhibition, the tumor cell responds by stimulating pathways with tumor progressing effects. At late stages of malignancy, tumor progression is driven by TGF-β overload. The tumor microenvironment is a target of TGF-β action that stimulates tumor progression via pro-tumorigenic effects on vascular, immune, and fibroblastic cells. Bone is one of the richest sources of TGF-β in the body and a common site for dissemination of breast cancer metastases. Osteoclastic degradation of bone matrix, which accompanies establishment and growth of metastases, triggers further release of bone-derived TGF-β. This leads to a vicious positive feedback of tumor progression, driven by ever increasing levels of TGF-β released from both the tumor and bone matrix. It is for this reason, that pharmaceutical companies have developed therapeutic agents that block TGF-β signaling. Nonetheless, the choice of drug design and dosing strategy can affect the efficacy of TGF-β therapeutics. This review will describe pre-clinical and clinical data of four major classes of TGF-β inhibitor, namely i) ligand traps, ii) antisense oligonucleotides, iii) receptor kinase inhibitors and iv) peptide aptamers. Long term dosing strategies with TGF-β inhibitors may be ill-advised, since this class of drug has potentially highly pleiotropic activity, and development of drug resistance might potentiate tumor progression. Current paradigms for the use of TGF-β inhibitors in oncology have therefore moved towards the use of combinatorial therapies and short term dosing, with considerable promise for the clinic.

show abstract

“…The region lost in chromosome 3 (p12.3-13) has been reported to exhibit imbalances in MCF-7 cells developing resistance to tamoxifen (63); the region 8p11-21 encodes the frizzled-related gene FRP1/FRZB, that is turned off in 78% of breast carcinomas (64), and associated with androgen in prostate cancer (65); the loss of chromosome arm 18q is a common event in primary breast cancers (60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70), ductal hyperplasia (71), and in breast cancer cell lines (72), and it is often interpreted as representing loss of one or more tumor-suppressor genes. The relevance of these losses in estrogen-induced cell transformation is that among the genes located in the q arm of chromosome 18 are two independent tumor-suppressor loci in segment 18q21.1, one at SMAD4 and the other potentially at an enhancer of DCC or an unrelated novel gene (66,70).…”

Section: Genomic Changes During the Tumorigenic Stage Of Malignant Trmentioning

confidence: 99%

The role of estrogen in the initiation of breast cancer

Russo

2006

The Journal of Steroid Biochemistry and Molecular Biology

485

302

View full text Add to dashboard Cite

Estrogens are considered to play a major role in promoting the proliferation of both the normal and the neoplastic breast epithelium. Their role as breast carcinogens has long been suspected and recently confirmed by epidemiological studies. Three major mechanisms are postulated to be involved in their carcinogenic effects: stimulation of cellular proliferation through their receptor-mediated hormonal activity, direct genotoxic effects by increasing mutation rates through a cytochrome P450-mediated metabolic activation, and induction of aneuploidy. Recently it has been fully demonstrated that estrogens are carcinogenic in the human breast by testing in an experimental system the natural estrogen 17β-estradiol (E 2 ) by itself or its metabolites 2-hydroxy, 4-hydroxy, and 16-a-hydroxyestradiol (2-OH-E 2, 4-OH-E 2, and 16-α-OH E 2 ) respectively, by inducing neoplastic transformation of human breast epithelial cells (HBEC) MCF10F in vitro to a degree at least similar to that induced by the chemical carcinogen benz(a)pyrene (BP). Neither TAMOXYFEN (TAM) nor ICI-182,780 abrogated the transforming efficiency of estrogen or its metabolites. The E 2 induced expression of anchorage independent growth, loss of ductulogenesis in collagen, invasiveness in Matrigel, is associated with the loss of 9p11-13 and only invasive cells that exhibited a 4p15.3-16 deletion were tumorigenic. Tumors were poorly differentiated ER-α and progesterone receptor negative adenocarcinomas that expressed keratins, EMA and E-cadherin. The E 2 induced tumors and tumorderived cell lines exhibited loss of chromosome 4, deletions in chromosomes 3p12.3-13, 8p11.1-21, 9p21-qter, and 18q, and gains in 1p, and 5q15-qter. The induction of complete transformation of the human breast epithelial cell MCF-10F in vitro confirms the carcinogenicity of E 2 , supporting the concept that this hormone could act as an initiator of breast cancer in women. This model provides a unique system for understanding the genomic changes that intervene for leading normal cells to tumorigenesis and for testing the functional role of specific genomic events taking place during neoplastic transformation. Keywordsestrogen; invasiveness; CGH; breast cancer 1.IntroductionBreast cancer is a malignancy whose dependence on ovarian function was first recognized through the regression of both advanced cancer (1) and metastatic disease (2) induced by oophorectomy in premenopausal women. Ulterior correlation of ovarian function with estrogen (1) To whom correspondence must be addressed: Jose Russo, M.D., F.C. A.P. Director, Breast Cancer Research Laboratory, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA, Phone: 215-728-4782, Fax: 215-728-2180, E-Mail: j_russo@fccc.edu Grant Numbers and Sources of support: This work was supported by the U.S. Army Medical and Research Materiel Command under grants DAMD17-00-1-0247 and DAMD17-03-1-0229.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a servi...

show abstract

Two somatic biallelic lesions within and near SMAD4 in a human breast cancer cell line

Cited by 10 publications

References 37 publications

Dual effects of TGF-β on ERα-mediated estrogenic transcriptional activity in breast cancer

Dual effects of TGF-β on ERα-mediated estrogenic transcriptional activity in breast cancer

Complexities of TGF-β Targeted Cancer Therapy

The role of estrogen in the initiation of breast cancer

Contact Info

Product

Resources

About