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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Most breast cancers arise from luminal epithelial cells and 25-30% of these tumours overexpress the ErbB-2 receptor. Herein, a non-transformed, immortalized cell system was used to investigate the effects of ErbB-2 overexpression in luminal epithelial cells. The phenotypic consequence of ErbB-2 overexpression is a shortening of the G1 phase of the cell cycle and early S phase entry, which leads to hyperproliferation. We show that this effect was mediated through the up-regulation of cdk6 and cyclins D1 and E, and enhanced degradation and relocalization of p27(Kip1). These changes were effected predominantly through enhanced MAPK signalling, resulting in cdk2 hyperactivation. PI3K signalling also participated in cell cycle progression, since PI3K and MAPK coordinately regulated changes in cyclin D1 and cdk6 expression. Cdk4 activity was not required for cell cycle progression in these cells, and was constitutively inhibited through its association with p16(INK4A). MAPK-dependent induction of p21(Cip1) was also necessary for G1 phase progression, although its degradation by the proteasome was required for S phase entry. These data provide new insights into the complex molecular mechanisms underlying mitogenic cell cycle control in luminal epithelial cells, the cell type relevant to primary breast cancer, and show how ErbB-2 overexpression subverts this normal control.
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PMID:Effects of ErbB-2 overexpression on mitogenic signalling and cell cycle progression in human breast luminal epithelial cells. 1224 55

Soy isoflavone, genistein has been shown to induce growth inhibition, cell cycle arrest and apoptosis in cultured cancer cell lines derived from head and neck, breast, lung, and prostate cancers and showed antitumor activity against tumors in multiple animal models. In the present study we show that genistein inhibits the growth of MCF-7 breast cancer cell line in a dose dependent manner. The genistein induced growth inhibition is accompanied by the reduction in the number of mitotic cells and overexpression of cyclin dependent kinase inhibitor p21WAF1 leading to cell cycle arrest. In addition, the telomeric area was significantly reduced in genistein treated MCF-7 cells. Analysis of multiple genes involving the apoptotic pathway reveals inhibition of Akt activity without affecting the steady state levels of Akt protein expression and the down regulation of proapoptotic gene BAD expression. From these results, we conclude that genistein-induced inhibition of cell division is partly mediated by decreased telomere length, reduced mitosis and inhibition of Akt activation, leading to induction of apoptosis.
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PMID:Pleotropic effects of genistein on MCF-7 breast cancer cells. 1279 5

Most human tumors display inactivation of the p53 and the p16(INK4)/pRb pathway. The Ink4a/alternative reading frame (ARF) locus encodes the p16(INK4a) and p14(ARF) (murine p19(ARF)) proteins. p16(INK4a) is deleted in 40-60% of breast cancer cell lines, and p16(INK4a) inactivation by DNA methylation occurs in < or =30% of human breast cancers. In mice genetically heterozygous for p16(INK4a) or Ink4a/Arf, predisposition to specific tumor types is enhanced. Ink4a/Arf(+/-) mice have increased E micro -Myc-induced lymphomagenesis and epidermal growth factor receptor-induced gliomagenesis. ErbB2 (epidermal growth factor receptor-related protein B2) is frequently overexpressed in human breast cancer and is sufficient for mammary tumorigenesis in vivo. We determined the role of heterozygosity at the Ink4a/Arf locus in ErbB2-induced mammary tumorigenesis. Compared with mouse mammary tumor virus-ErbB2 Ink4a/Arf(+/-) mice, mouse mammary tumor virus-ErbB2 Ink4a/Arf(wt) mammary tumors showed increased p16(INK4a), reduced Ki-67 expression, and reduced cyclin D1 protein but increased mammary tumor apoptosis with no significant change in the risk of developing mammary tumors. These studies demonstrate the contribution of Ink4a/Arf heterozygosity to tumor progression is tissue specific in vivo. In view of the important role of Ink4a/Arf in response to chemotherapy, these transgenic mice may provide a useful model for testing breast tumor therapies.
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PMID:The role of Ink4a/Arf in ErbB2 mammary gland tumorigenesis. 1281 Jun 76

Breast tissue from healthy women contains variant mammary epithelial cells (vHMEC) exhibiting p16INK4a promoter hypermethylation both in vivo and in vitro. When continuously cultured, vHMEC acquire telomeric dysfunction and produce the types of chromosomal abnormalities seen in premalignant lesions of cancer. We find that late passage vHMEC express elevated prostaglandin cyclo-oxygenase 2 (COX-2), which contributes to increased prostaglandin synthesis, angiogenic activity, and invasive ability. These data demonstrate the existence of human mammary epithelial cells with the potential to acquire multiple genomic alterations and phenotypes associated with malignant cells. Moreover, COX-2 overexpression coincides with focal areas of p16INK4a hypermethylation in vivo, creating ideal candidates as precursors to breast cancer. These putative precursors can be selectively eliminated upon exposure to COX-2 inhibitors in vitro.
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PMID:Histologically normal human mammary epithelia with silenced p16(INK4a) overexpress COX-2, promoting a premalignant program. 1505 Sep 18

p16INK4a, a cell cycle inhibitor that inhibits cyclin-dependent kinase 4 (cdk4) and cdk6, has been found as the tumor suppressor gene and is frequently deleted, methylated or mutated in many malignancies. Since p16INK4a is also a key element controlling cellular senescence and other functions, we hypothesized that p16INK4a induced tumor suppression may not be limited to the inhibition of cdks. To investigate the role of p16INK4a in tumor suppression and the potential interaction between p16INK4a and other cellular controlling elements, such as telomerase activity and DNA repair ability, the full-length of p16INK4a cDNA was cloned into a retroviral vector and introduced into human breast cancer MCF-7 cells that were previously demonstrated to harbor homozygous deletions of the p16INK4a gene. Stable expression of p16INK4a suppressed the malignant phenotype in MCF-7 cells, including cell proliferation, anchorage-independent growth, G1/G0 cell cycle arrest, and the blockage of pRB phosphorylation. In addition, expression of p16INK4a suppressed telomerase activity and restored the telomere shortening process, and decreased cell DNA repair ability and sensitized cells to the DNA damage reagent. Our data suggest that the wild-type p16INK4a plays an important role in suppression of tumor malignancy, not only by inhibiting cell proliferation through cell cycle arrest, but also by inhibiting other cellular controlling mechanisms, such as telomerase activity and DNA repair capacity.
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PMID:Wild-type p16INK4a suppresses cell growth, telomerase activity and DNA repair in human breast cancer MCF-7 cells. 1513 5

The p16-cyclin D-Cdk4(6)-pRB-E2F and p73 pathways are involved in the control of cell-cycle progression, and genetic lesions in both pathways frequently occur in breast carcinomas and other human cancers. The p16INK4a gene is involved in regulation of the G1/S transition, and when overexpressed, the p73 gene activates transcription of p53-responsive genes and promotes apoptosis. These pathways are related, for instance, p73 is also downstream of E2F-1, since E2F-1 induces p73-mediated apoptosis in the absence of p53. We studied 93 breast cancer patients to identify alterations in the expression of p16INK4a and p73 by semiquantitative RT-PCR analysis and possible interactions between them and correlations with clinicopathological parameters. p73 was overexpressed in 24 cases. Overexpression of p16INK4a was detected in 17 cases and underexpression in 32 cases. A significant correlation was observed between the overexpression of both genes (P = 0.05). Concurrent overexpression of p73 and p16INK4a was significantly correlated with metastases in three or more lymph nodes (P = 0.0007), positive immunohistochemistry for p53 (P = 0.014), vascular invasion (P = 0.048) and negative progesterone receptors (P = 0.004). These results indicate that concomitant overexpression of p16INK4a and p73 may be involved in breast cancer and associated with poor tumor characteristics.
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PMID:Overexpression of p16INK4a correlates with high expression of p73 in breast carcinomas. 1545 Apr 20

A recent report suggests that, in an in vitro model of premalignant breast cells (vHMECs), silencing of INK4A gene is accompanied by over-expression of cyclo-oxygenase (COX)-2. This suggests that COX-2 over-expression may be an early event in breast cancer aetiology permitting clones within the normal epithelium to evade apoptosis, to increase their numbers and perhaps acquire further changes that promote the formation of hyperplasias, and eventually carcinomas. While COX-2 expression in normal breast epithelium in vivo has not been proven to be linked to an increased risk of breast cancer, its over-expression in the premalignant model in vitro does provide preliminary evidence that COX-2 inhibition may be a useful chemoprevention strategy.
Breast Cancer Res 2005
PMID:Do early premalignant changes in normal breast epithelial cells predict cancer development? 1564 77

The difficulty to dissect a complex phenotype of established malignant cells to several critical transcriptional programs greatly impedes our understanding of the malignant transformation. The genetic elements required to transform some primary human cells to a tumorigenic state were described in several recent studies. We took the advantage of the global genomic profiling approach and tried to go one step further in the dissection of the transformation network. We sought to identify the genetic signatures and key target genes, which underlie the genetic alterations in p53, Ras, INK4A locus, and telomerase, introduced in a stepwise manner into primary human fibroblasts. Here, we show that these are the minimally required genetic alterations for sarcomagenesis in vivo. A genome-wide expression profiling identified distinct genetic signatures corresponding to the genetic alterations listed above. Most importantly, unique transformation hallmarks, such as differentiation block, aberrant mitotic progression, increased angiogenesis, and invasiveness, were identified and coupled with genetic signatures assigned for the genetic alterations in the p53, INK4A locus, and H-Ras, respectively. Furthermore, a transcriptional program that defines the cellular response to p53 inactivation was an excellent predictor of metastasis development and bad prognosis in breast cancer patients. Deciphering these transformation fingerprints, which are affected by the most common oncogenic mutations, provides considerable insight into regulatory circuits controlling malignant transformation and will hopefully open new avenues for rational therapeutic decisions.
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PMID:Transcriptional programs following genetic alterations in p53, INK4A, and H-Ras genes along defined stages of malignant transformation. 1635 73

Normal human mammary epithelial cells (HMECs) have a finite life span and do not undergo spontaneous immortalization in culture. Critical to oncogenic transformation is the ability of cells to overcome the senescence checkpoints that define their replicative life span and to multiply indefinitely -- a phenomenon referred to as immortalization. HMECs can be immortalized by exposing them to chemicals or radiation, or by causing them to overexpress certain cellular genes or viral oncogenes. However, the most efficient and reproducible model of HMEC immortalization remains expression of high-risk human papillomavirus (HPV) oncogenes E6 and E7. Cell culture models have defined the role of tumor suppressor proteins (pRb and p53), inhibitors of cyclin-dependent kinases (p16INK4a, p21, p27 and p57), p14ARF, telomerase, and small G proteins Rap, Rho and Ras in immortalization and transformation of HMECs. These cell culture models have also provided evidence that multiple epithelial cell subtypes with distinct patterns of susceptibility to oncogenesis exist in the normal mammary tissue. Coupled with information from distinct molecular portraits of primary breast cancers, these findings suggest that various subtypes of mammary cells may be precursors of different subtypes of breast cancers. Full oncogenic transformation of HMECs in culture requires the expression of multiple gene products, such as SV40 large T and small t, hTERT (catalytic subunit of human telomerase), Raf, phosphatidylinositol 3-kinase, and Ral-GEFs (Ral guanine nucleotide exchange factors). However, when implanted into nude mice these transformed cells typically produce poorly differentiated carcinomas and not adenocarcinomas. On the other hand, transgenic mouse models using ErbB2/neu, Ras, Myc, SV40 T or polyomavirus T develop adenocarcinomas, raising the possibility that the parental normal cell subtype may determine the pathological type of breast tumors. Availability of three-dimensional and mammosphere models has led to the identification of putative stem cells, but more studies are needed to define their biologic role and potential as precursor cells for distinct breast cancers. The combined use of transformation strategies in cell culture and mouse models together with molecular definition of human breast cancer subtypes should help to elucidate the nature of breast cancer diversity and to develop individualized therapies.
Breast Cancer Res 2005
PMID:Mammary epithelial cell transformation: insights from cell culture and mouse models. 1598 72

In breast cancer, cyclins D1 and E and the cyclin-dependent kinase inhibitors p21 (Waf1/Cip1)and p27 (Kip1) are important in cell-cycle control and as potential oncogenes or tumor suppressor genes. They are regulated in breast cancer cells following mitogenic stimuli including activation of receptor tyrosine kinases and steroid hormone receptors, and their deregulation frequently impacts on breast cancer outcome, including response to therapy. The cyclin-dependent kinase inhibitor p16 (INK4A) also has a critical role in transformation of mammary epithelial cells. In addition to their roles in cell cycle control, some of these molecules, particularly cyclin D1, have actions that are not mediated through regulation of cyclin-dependent kinase activity but may be important for loss of proliferative control during mammary oncogenesis.
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PMID:Cell cycle control in breast cancer cells. 1626 37


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