Scaffold attachment factor B1 functions in development, growth, and reproduction.

Scaffold attachment factor B1 (SAFB1) is a multifunctional protein that can bind both DNA and RNA and is involved in RNA processing and stress response. In addition, SAFB1 contains a transcriptional repression domain and can bind certain hormone receptors and repress their activity. To assess the role of SAFB1 in vivo, we generated SAFB1 mutant mice through targeted deletion in embryonic stem cells.

Effect of 4-(5-chloro-2-hydroxyphenyl)-3-(2-hydroxyethyl)-6-(trifluoromethyl)-quinolin-2(1H)-one (BMS-223131), a novel opener of large conductance Ca2+-activated K+ (maxi-K) channels on normal and stress-aggravated colonic motility and visceral nociception.

We evaluated the effects of 4-(5-chloro-2-hydroxyphenyl)-3-(2-hydroxyethyl)-6-(trifluoromethyl)-quinolin-2(1H)-one (BMS-223131), an opener of large conductance Ca(2+)-activated potassium (maxi-K) channels, on normal and stress-exacerbated colonic motility and visceral nociception in the rat. Fecal output was employed as an index of motility. Visceral nociception, in response to intracolonic balloon distension (10-90 mm Hg; 30 s duration), was evaluated using one of three indices: change in blood pressure, abdominal withdrawal, or myoelectrical activity.

Cross talk between estrogen receptor and IGF signaling in normal mammary gland development and breast cancer.

Both estrogen and insulin-like growth factor-1 (IGF-I) are critical for normal mammary gland development, but are also implicated in breast cancer development and progression. Evidence that the signaling pathways utilized by these hormones interact has been shown in normal and tumorigenic cell lines, xenograft models, and breast cancer tissue. Analysis of the mechanism of interaction between estrogen and IGF-I has revealed multiple levels of cross-talk with bi-directional regulation of both pathways.

Bisphenol-A and estradiol exert novel gene regulation in human MCF-7 derived breast cancer cells.

Xenoestrogens such as bisphenol-A (BPA) can mimic endogenous 17beta-estradiol (E2) in vitro and in vivo through binding the estrogen receptor (ER), and modulating target gene expression. In the present study, we compared global gene regulation by BPA and E2 in estrogen responsive (ERalpha-HA) human breast cancer cells derived from the MCF-7 cell line. The ERalpha-HA cells (stably over-expressing ERalpha) were exposed to E2 (10(-8)M) or BPA (10(-6)M), for 3h followed by analysis of global gene expression.

Structure-function analysis of the estrogen receptor alpha corepressor scaffold attachment factor-B1: identification of a potent transcriptional repression domain.

Scaffold attachment factor-B1 (SAFB1) is a nuclear matrix protein that has been proposed to couple chromatin structure, transcription, and RNA processing. We have previously shown that SAFB1 can repress estrogen receptor (ERalpha)-mediated transactivation. Here we present a structure-function study showing that transactivation is mediated via an intrinsic and transferable C-terminal repression domain (RD).

AIB1/SRC-3 deficiency affects insulin-like growth factor I signaling pathway and suppresses v-Ha-ras-induced breast cancer initiation and progression in mice.

Although the amplified in breast cancer 1 (AIB1) coactivator is amplified and overexpressed in breast cancers, its role in mammary carcinogenesis remains unknown. We demonstrate that during mammary development and tumorigenesis, the elevation of AIB1 level and its nuclear localization correlate with normal and transformed mammary epithelial proliferation, whereas its lower expression and cytoplasmic localization correlate with mammary epithelial quiescence and differentiation. In this study, the role of AIB1 in breast tumor initiation, progression, and metastasis was studied by generating AIB1(+/+), AIB1(+/-), and AIB1(-/-) mice harboring the mouse mammary tumor virus/v-Ha-ras (ras) transgene that induces breast tumors.

26th Annual San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 3-6 December 2003: update on preclinical and translational research.

The San Antonio Breast Cancer Symposium is the largest annual meeting devoted solely to breast cancer research. The late William L McGuire's vision for this meeting was to stimulate 'translational research', many years before this term became popular. In this way, the San Antonio Breast Cancer Symposium represents a forum in which basic and clinical researchers present their research side by side.

Regulatory nodes that integrate and coordinate signaling as potential targets for breast cancer therapy.

Blockade of the estrogen receptor (ER) with antiestrogens and aromatase inhibitors is effective in the treatment of breast cancer. Why ER plays such a dominant role in breast cancer and represents such an excellent target remains to be defined. The ability of ER to respond to multiple inputs and to control expression of multiple downstream genes may be one of the reasons why ER is such a powerful target for breast cancer treatment.

Increases in estrogen receptor-alpha concentration in breast cancer cells promote serine 118/104/106-independent AF-1 transactivation and growth in the absence of estrogen.

A common phenotype in breast cancer is the expansion of the estrogen receptor-alpha (ER+) cell population and an inappropriate elevation of ERalpha protein, the latter predisposing patients for a poorer prognosis than those with lower levels of the receptor. A tetracycline-inducible ERalpha overexpression model was developed in the MCF-7 cell line to assess induction of endogenous gene activation and growth in response to elevations in ERalpha protein. Heightened levels of ERalpha resulted in aberrant promoter occupancy and gene activation in the absence of hormone, which was independent of ligand and AF-2 function.

Rapid induction of IGF-IR signaling in normal and tumor tissue following intravenous injection of IGF-I in mice.

The detection of IGF-IR signaling in animal models has important implications for determining the role of this receptor in normal physiology and tumor growth. While many reports have correlated changes in plasma IGF-I levels in vivo with biological responses, few have shown that altered IGF-I levels can directly affect signaling within normal or tumor tissue. Here, we present new data that shows how the intravenous (IV) injection of IGF-I can be used to directly examine IGF signaling at the tissue level.

A dominant negative type I insulin-like growth factor receptor inhibits metastasis of human cancer cells.

We have previously shown that LCC6 wild-type (WT) cells, a metastatic variant of MDA-MB-435 cancer cells originally derived from a breast cancer patient, exhibit enhanced motility in response to IGF-I compared with the parent MDA-MB-435 cells. To further understand the role of the type I insulin-like growth factor (IGF) receptor (IGF1R) in cancer metastasis we inhibited signaling via IGF1R using a C-terminal-truncated IGF1R. The truncated receptor retains the ligand binding domain but lacks the autophosphorylated tyrosine residues in the carboxyl terminus.

Progesterone crosstalks with insulin-like growth factor signaling in breast cancer cells via induction of insulin receptor substrate-2.

Both progesterone and the insulin-like growth factors (IGFs) are critically involved in mammary gland development and also in breast cancer progression. However, how the progesterone and IGF signaling pathways interact with each other to regulate breast cancer cell growth remains unresolved. In this study, we investigated progesterone regulation of IGF signaling components in breast cancer cells.

Estrogen-mediated down-regulation of E-cadherin in breast cancer cells.

E-cadherin is an important mediator of cell-cell interactions, and has been shown to play a crucial role in breast tumor suppression. Its inactivation occurs through instability at its chromosomal locus and mutations, but also through epigenetic mechanisms such as promoter hypermethylation and transcriptional silencing. We show here that the potent mitogen estrogen causes down-regulation of E-cadherin levels in both normal and tumorigenic breast epithelial cells, and that this down-regulation is reversed by antiestrogens.

Developmental and hormonal signals dramatically alter the localization and abundance of insulin receptor substrate proteins in the mammary gland.

Insulin receptor substrates (IRS) are central integrators of hormone, cytokine, and growth factor signaling. IRS proteins can be phosphorylated by a number of signaling pathways critical to normal mammary gland development. Studies in transgenic mice that overexpress IGF-I in the mammary gland suggested that IRS expression is important in the regulation of normal postlactational mammary involution.

SAFB2, a new scaffold attachment factor homolog and estrogen receptor corepressor.

We have characterized previously the nuclear matrix protein/scaffold attachment factor (SAFB) as an estrogen receptor corepressor and as a potential tumor suppressor gene in breast cancer. A search of the human genome for other potential SAFB family members revealed that KIAA00138 (now designated as SAFB2) has high homology to SAFB (now designated as SAFB1). SAFB1 and SAFB2 are mapped adjacent to each other on chromosome 19p13.

Local insulin-like growth factor-II mediates prolactin-induced mammary gland development.

Prolactin (PRL) is a major determinant of mammary epithelial cell proliferation during alveolar development in sexually mature and pregnant mice. To date, it has not been clear whether PRL effects these responses alone or by also invoking the action of autocrine/paracrine growth factors. In this study, we provide evidence that part of the effect of PRL on mammary gland growth is mediated by IGF-II.

Insulin-like growth factor-I inhibits progesterone receptor expression in breast cancer cells via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway: progesterone receptor as a potential indicator of growth factor activity in breast cancer.

Although interactions between estrogen and growth factor signaling pathways have been studied extensively, how growth factors and progesterone regulate each other is less clear. In this study, we found that IGF-I sharply lowers progesterone receptor (PR) mRNA and protein levels in breast cancer cells. Other growth factors, such as epidermal growth factor, also showed the same effect.

New mechanisms of signal transduction inhibitor action: receptor tyrosine kinase down-regulation and blockade of signal transactivation.

The explosion of signal transduction research over the last 10 years has provided a unique insight into the complexity of these intricate pathways. Whereas intermediates of multiple signaling pathways have been identified, understanding their function and, in particular, the interactions between them has become a daunting task. The increasing evidence that many of these pathways can cross-talk with each other via signal transactivation inevitably raises the question of how cells determine specificity in signaling.

Disruption of steroid and prolactin receptor patterning in the mammary gland correlates with a block in lobuloalveolar development.

Targeted deletion of the bZIP transcription factor, CCAAT/enhancer binding protein-beta (C/EBPbeta), was shown previously to result in aberrant ductal morphogenesis and decreased lobuloalveolar development, accompanied by an altered pattern of progesterone receptor (PR) expression. Here, similar changes in the level and pattern of prolactin receptor (PrlR) expression were observed while screening for differentially expressed genes in C/EBPbeta(null) mice. PR patterning was also altered in PrlR(null) mice, as well as in mammary tissue transplants from both PrlR(null) and signal transducer and activator of transcription (Stat) 5a/b-deficient mice, with concomitant defects in hormone-induced proliferation.

Cross-talk among estrogen receptor, epidermal growth factor, and insulin-like growth factor signaling in breast cancer.

Since the cloning of the estrogen receptor alpha (ERalpha) and subsequent identification of a second distinct form of ER, termed ERbeta, a large volume of research has begun to define the molecular mechanisms of ER action. However, although great progress has been made, ER action is still poorly understood. It is expected that a better understanding of ER action may lead to novel strategies and targets for breast cancer prevention and treatment.