Role of TGFβ in the anti-estrogen response/resistance of human breast cancer

Benson, John R.; Baum, Michael; Colletta, Anthony A.

doi:10.1007/bf02017394

Cited by 15 publications

(3 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, oestrogen and progesterone together with TGF␤ are necessary for the maintenance of p53 activity in mammary epithelium and thus the ability to sense and respond appropriately to DNA damage [11]. This crosstalk is also consistent with the observation that the action of tamoxifen is at least partially mediated through activation of TGF␤ [12].…”

Section: Page 2 Ofsupporting

confidence: 82%

Review of: Proliferation of estrogen receptor-alpha-positive mammary epithelial cells is restrained by transforming growth factor-beta1 in adult mice

Kalirai

Clarke

2006

Breast Cancer Online

View full text Add to dashboard Cite

Citation of original article:K. B. Ewan, H. A. Oketch-Rabah, S. A. Ravani, G. Shyamala, H. L. Moses, M. H. Barcellos-Hoff. Proliferation of estrogen receptor-alpha-positive mammary epithelial cells is restrained by transforming growth factor-beta1 in adult mice.American Journal of Pathology2005;167(2): 409–17.Abstract of the original article:Transforming growth factor (TGF)-beta1 is a potent inhibitor of mammary epithelial proliferation. In human breast, estrogen receptor (ER)-alpha cells rarely co-localize with markers of proliferation, but their increased frequency correlates with breast cancer risk. To determine whether TGF-beta1 is necessary for the quiescence of ER-alpha-positive populations, we examined mouse mammary epithelial glands at estrus. Approximately, 35% of epithelial cells showed TGF-beta1 activation, which co-localized with nuclear receptor-phosphorylated Smad 2/3, indicating that TGF-beta signaling is autocrine. Nuclear Smad co-localized with nuclear ER-alpha. To test whether TGF-beta inhibits proliferation, we examined genetically engineered mice with different levels of TGF-beta1. ER-alpha co-localization with markers of proliferation (i.e., Ki-67 or bromodeoxyuridine) at estrus was significantly increased in the mammary glands of TGF-beta1 C57/bl/129SV heterozygote mice. This relationship was maintained after pregnancy but was absent at puberty. Conversely, mammary epithelial expression of constitutively active TGF-beta1 via the MMTV promoter suppressed proliferation of ER-alpha-positive cells. Thus, TGF-beta1 activation functionally restrains ER-alpha-positive cells from proliferating in adult mammary gland. Accordingly, we propose that TGF-beta1 dysregulation may promote proliferation of ER-alpha-positive cells associated with breast cancer risk in humans.

show abstract

Section: Page 2 Ofsupporting

confidence: 82%

Review of: Proliferation of estrogen receptor-alpha-positive mammary epithelial cells is restrained by transforming growth factor-beta1 in adult mice

Kalirai

Clarke

2006

Breast Cancer Online

View full text Add to dashboard Cite

show abstract

“…Estrogens also act as mitogens to promote cell proliferation in both normal breast tissue and breast carcinomas, and ER␣ is a prognostic marker and therapeutic target for breast cancer (10,11). In contrast, transforming growth factor-␤ (TGF-␤) is an inhibitor of cell cycle progression in epithelial cells and antagonizes the mitogenic effect of ER␣ (12,13). Loss of responsiveness to TGF-␤ is believed to be a major factor in tumor formation and progression (14 -17).…”

mentioning

confidence: 99%

Smad4 Inhibits Tumor Growth by Inducing Apoptosis in Estrogen Receptor-α-positive Breast Cancer Cells

Oelschlager

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

Estrogen is a mitogen in most estrogen receptor-␣ (ER␣)-Estrogens regulate differentiation and maintenance of reproductive, skeletal, and other tissues by activating their receptors (1). Ligands of estrogen receptors (ERs) 1 induce binding of ERs to specific DNA response elements to regulate target gene expression (2, 3). The DNA-bound receptor can then either positively or negatively regulate target gene transcription in specific cells or tissues. Agonist-bound ER in breast cancer cells recruits transcriptional coactivators. Conversely, when occupied by antagonists, the DNA-bound receptor actively recruits corepressors, resulting in suppression of gene transcription (4 -6). Structural studies indicate that estrogen and tamoxifen induce distinct conformational changes in ER␣ (7). In turn, these distinct conformations determine the recruitment of coactivators or corepressors, thereby leading to their diverse biological effects. Estrogen antagonists such as tamoxifen have been clinically effective in halting or delaying the progression of breast cancer (8, 9). Estrogens also act as mitogens to promote cell proliferation in both normal breast tissue and breast carcinomas, and ER␣ is a prognostic marker and therapeutic target for breast cancer (10, 11). In contrast, transforming growth factor-␤ (TGF-␤) is an inhibitor of cell cycle progression in epithelial cells and antagonizes the mitogenic effect of ER␣ (12, 13). Loss of responsiveness to TGF-␤ is believed to be a major factor in tumor formation and progression (14 -17). We have shown that Smad4 acts as a corepressor in vivo by interacting with ER␣ and repressing estrogen-induced transcriptional activity (18). Smad4 is the common signal transducer for both TGF-␤ and bone morphogenetic protein and is also known as a tumor suppressor. In Smad4 mammary epithelium conditional knock-out mice, almost 100% of female mice develop squamous cell carcinomas and mammary abscesses. However, male knock-out mice only rarely develop tumors and abscesses (19). In this study, we demonstrate that Smad4 inhibits breast tumor growth in nude mice by inducing apoptosis in ER␣-positive cells. Furthermore, we show that Smad4 induces expression of the pro-apoptotic proteins Bim and Bax and release of cytochrome c in ER␣-positive (but not ER␣-negative) cells. Our results indicate that ER␣ is required for Smad4-induced apoptosis in breast cancer cells. MATERIALS AND METHODSCell Culture-All human breast cancer cell lines used in this study were originally obtained from American Type Culture Collection. MCF-7 and MDA-MB-231 cells were cultured at 37°C and 5% CO 2 in RPMI 1640 medium and Dulbecco's modified Eagle's medium, respectively, Both media were supplemented with 10% fetal bovine serum, 100 IU/ml penicillin, and 100 g/ml streptomycin.Transfection and Retroviral Infection-Retrovirus containing ⌬3-green fluorescent protein (GFP) or ⌬3-Smad4 was overlaid with MCF-7, T47D, MDA-MB-231, and MDA-MB-468 cells for 4 h at 37°C. The infection medium was replaced with 3 ml of complete RPMI 1640 med...

show abstract

“…The anticancer effects of genistein in vitro (Wei et al, 1993) are attributed to its inhibitory effects on enzymes that play a role in signal transduction, including ribosomal S6 kinase (Linassier et al, 1990), MAP kinase (Thorburn and Thorburn, 1994), and tyrosine protein kinases (Akiyama et al, 1987). Genistein also inhibits the activity of DNA topoisomerase II (Constantinou et al, 1990) and raises the in vitro concentrations of transforming growth factor (TGF ) (Peterson et al, 1998) which may suppress growth of cancer cells (Benson and Colletta, 1995;Benson et al, 1996;Markowitz and Roberts, 1997). Genistein has an important role as a potent inhibitor of angiogenesis in vitro (Messina, 1999).…”

Section: Saponinsmentioning

confidence: 99%