Approximately 75% of breast tumors express the estrogen receptor (ER), and women with these tumors will receive endocrine therapy. Unfortunately, up to 50% of these patients will fail ER-targeted therapies due to either de novo or acquired resistance. ER-positive tumors can be classified based on gene expression profiles into Luminal A- and Luminal B-intrinsic subtypes, with distinctly different responses to endocrine therapy and overall patient outcome. However, the underlying biology causing this tumor heterogeneity has yet to become clear. This review will explore the role of inflammation as a risk factor in breast cancer as well as a player in the development of more aggressive, therapy-resistant ER-positive breast cancers. First, breast cancer risk factors, such as obesity and mammary gland involution after pregnancy, which can foster an inflammatory microenvironment within the breast, will be described. Second, inflammatory components of the tumor microenvironment, including tumor-associated macrophages and proinflammatory cytokines, which can act on nearby breast cancer cells and modulate tumor phenotype, will be explored. Finally, activation of the nuclear factor κB (NF-κB) pathway and its cross talk with ER in the regulation of key genes in the promotion of more aggressive breast cancers will be reviewed. From these multiple lines of evidence, we propose that inflammation may promote more aggressive ER-positive tumors and that combination therapy targeting both inflammation and estrogen production or actions could benefit a significant portion of women whose ER-positive breast tumors fail to respond to endocrine therapy.
FSH and IGF-I synergistically stimulate gonadal steroid production; conversely, silencing the FSH or the IGF-I genes leads to infertility and hypogonadism. To determine the molecular link between these hormones, we examined the signaling cross talk downstream of their receptors. In human and rodent granulosa cells (GCs), IGF-I potentiated the stimulatory effects of FSH and cAMP on the expression of steroidogenic genes. In contrast, inhibition of IGF-I receptor (IGF-IR) activity or expression using pharmacological, genetic, or biochemical approaches prevented the FSH- and cAMP-induced expression of steroidogenic genes and estradiol production. In vivo experiments demonstrated that IGF-IR inactivation reduces the stimulation of steroidogenic genes and follicle growth by gonadotropins. FSH or IGF-I alone stimulated protein kinase B (PKB), which is also known as AKT and in combination synergistically increased AKT phosphorylation. Remarkably, blocking IGF-IR expression or activity decreased AKT basal activity and abolished AKT activation by FSH. In GCs lacking IGF-IR activity, FSH stimulation of Cyp19 expression was rescued by overexpression of constitutively active AKT. Our findings demonstrate, for the first time, that in human, mouse, and rat GCs, the well-known stimulatory effect of FSH on Cyp19 and AKT depends on IGF-I and on the expression and activation of the IGF-IR.
Folliculogenesis is a lengthy process that requires the proliferation and differentiation of granulosa cells (GCs) for preovulatory follicle formation. The most crucial endocrine factor involved in this process is follicle-stimulating hormone (FSH). Interestingly, previous in vitro studies indicated that FSH does not stimulate GC proliferation in the absence of the insulinlike growth factor 1 receptor (IGF1R). To determine the role of the IGF1R in vivo, female mice with a conditional knockdown of the IGF1R in the GCs were produced and had undetectable levels of IGF1R mRNA and protein in the GCs. These animals were sterile, and their ovaries were smaller than those of control animals and contained no antral follicles even after gonadotropin stimulation. The lack of antral follicles correlated with a 90% decrease in serum estradiol levels. In addition, under a superovulation protocol no oocytes were found in the oviducts of these animals. Accordingly, the GCs of the mutant females expressed significantly lower levels of preovulatory markers including aromatase, luteinizing hormone receptor, and inhibin α. In contrast, no alterations in FSH receptor expression were observed in GCs lacking IGF1R. Immunohistochemistry studies demonstrated that ovaries lacking IGF1R had higher levels of apoptosis in follicles from the primary to the large secondary stages. Finally, molecular studies determined that protein kinase B activation was significantly impaired in mutant females when compared with controls. These in vivo findings demonstrate that IGF1R has a crucial role in GC function and, consequently, in female fertility.
The cumulus cell response to FSH resembles the differentiation of preantral to preovulatory granulosa cells. This differentiation program requires IGF1R activity and subsequent AKT activation.
Flexible filamentous viruses make up a large fraction of the known plant viruses, but in comparison with those of other viruses, very little is known about their structures. We have used fiber diffraction, cryo-electron microscopy, and scanning transmission electron microscopy to determine the symmetry of a potyvirus, soybean mosaic virus; to confirm the symmetry of a potexvirus, potato virus X; and to determine the low-resolution structures of both viruses. We conclude that these viruses and, by implication, most or all flexible filamentous plant viruses share a common coat protein fold and helical symmetry, with slightly less than 9 subunits per helical turn.Flexible filamentous plant viruses include at least 19 recognized genera (22), almost all in three families of singlestranded, positive-sense RNA viruses, the Potyviridae, the Flexiviridae, and the Closteroviridae. Members of the family Potyviridae account for almost a third of the total known plant virus species (22) and are responsible for more than half the viral crop damage in the world (37), infecting most economically important crops (32). Members of the family Flexiviridae (2), and particularly of the large genus Potexvirus, are also of considerable significance to agriculture (42). Both families show great potential for biotechnological applications, including protein expression and vaccine production (12, 54). Despite their importance, however, little is known about the structures of any of the flexible filamentous plant viruses, in sharp contrast to the amount of data on the rigid tobamoviruses (48,63) or the icosahedral plant viruses (15); flexibility, instability, and in many cases low levels of expression have made these viruses particularly intractable to structural studies. Structural and evolutionary relationships among the flexible filamentous plant viruses have been suggested (18,47,56,60), but there is very little sequence homology between the coat proteins of viruses in the different families, and there has hitherto been no structural support for such relationships at the level of either viral symmetry or coat protein folding. Indeed, reports of viral symmetry until now appeared to contradict hypotheses of evolutionary relationships.Soybean mosaic virus (SMV) is a potyvirus, that is, a member of the genus Potyvirus, the largest genus in the family Potyviridae (3). SMV is a major pathogen of soybeans, transmitted efficiently through seed and by aphids in a nonpersistent manner; yield losses as high as 35% have been reported (30). Despite dramatic morphological differences, members of the family resemble the icosahedral plant comoviruses and animal picornaviruses in genomic organization and replication strategy (32). Early electron microscopic observations found the potyviruses to be about 7,500 Å long and 120 Å in diameter, with helical pitches of about 34 Å (44, 60). A fiber diffraction study (51) of the tritimovirus wheat streak mosaic virus (WSMV) suggested that WSMV has 6.9 subunits per turn of the viral helix, but there was consider...
Constitutive activation of NFB in estrogen receptor (ER)-positive breast cancer is associated with tumor recurrence and development of anti-estrogen resistance. Furthermore, a gene expression signature containing common targets for ER and NFB has been identified and found to be associated with the more aggressive luminal B intrinsic subtype of ER-positive breast tumors. Here, we describe a novel mechanism by which ER and NFB cooperate to up-regulate expression of one important gene from this signature, ABCG2, which encodes a transporter protein associated with the development of drug-resistant breast cancer. We and others have confirmed that this gene is regulated primarily by estrogen in an ER-and estrogen response element (ERE)-dependent manner. We found that whereas proinflammatory cytokines have little effect on this gene in the absence of 17-estradiol, they can potentiate ER activity in an NFB-dependent manner. ER allows the NFB family member p65 to access a latent NFB response element located near the ERE in the gene promoter. NFB recruitment to the gene is, in turn, required to stabilize ER occupancy at the functional ERE. The result of this cooperative binding of ER and p65 at adjacent response elements leads to a major increase in both ABCG2 mRNA and protein expression. These findings indicate that estrogen and inflammatory factors can modify each other's activity through modulation of transcription factor accessibility and/or occupancy at adjacent response elements. This novel transcriptional mechanism could have important implications in breast cancer, where both inflammation and estrogen can promote cancer progression. The estrogen 17-estradiol (E 2 )2 is a steroid that plays an important role in reproductive tissues, as well as in the skeletal, cardiovascular, immune, and central nervous systems, by regulating a number of cellular processes, such as proliferation, differentiation, and survival. In the classical mechanism of estrogen action, E 2 binds to the estrogen receptor (ER) to promote receptor homodimerization. The ligand-bound receptor binds to cognate DNA sequences, called estrogen response elements (EREs), which leads to coregulator recruitment and target gene transcription. In addition to direct DNA binding, ER can also regulate gene transcription via protein-protein interaction with other DNA-binding transcription factors, such as the proteins of the AP-1 complex and Sp1 (1, 2).Estrogen can also modulate gene transcription by the proinflammatory transcription factor NFB, which, like ER, influences numerous cellular processes. In the classical NFB pathway, binding of proinflammatory cytokines to their receptors activates the IB kinase (IKK) complex, which phosphorylates the inhibitory protein IB, leading to its subsequent ubiquitination and proteasomal degradation. NFB family members p65 and p50 can then translocate to the nucleus and regulate transcription of a cohort of genes by binding to specific DNA elements called NFB response elements (NFBREs). Numerous studies in a variety of phy...
Estrogen receptor (ER) and NF-B are transcription factors with profound effects on breast cancer cell proliferation and survival. While many studies demonstrate that ER and NF-B can repress each other, we previously identified a gene signature that is synergistically upregulated by these two factors in more aggressive luminal B breast tumors. Herein, we examine a novel mechanism of cross talk between ER and NF-B that results in the upregulation of the antiapoptotic gene BIRC3 (also known as cIAP2). We demonstrate that NF-B, acting through two response elements, is required for ER recruitment to an adjacent estrogen response element (ERE) in the BIRC3 promoter. This effect is accompanied by a major increase in NF-B-dependent histone acetylation around the ERE. Interestingly, CBP, a histone acetyltransferase previously implicated in repressive interactions between ER and NF-B, plays a permissive role by promoting histone acetylation and ER recruitment, as well as enhanced expression of BIRC3. These findings suggest a new gene regulatory mechanism by which inflammation and NF-B activation can influence ER recruitment to inherently inactive ER binding sites. This fine-tuning mechanism may explain how two factors that generally repress each other's activity may work together on certain genes to promote breast cancer cell survival and tumor progression. T he estrogen receptor (ER) is expressed in approximately 75%of breast cancers, and women with such tumors are generally treated with endocrine therapies, such as tamoxifen or aromatase inhibitors. However, not all ER-positive tumors respond to these therapies. Through gene expression profiling studies, ER-positive tumors have been delineated into two intrinsic subtypes, luminal A and luminal B (48, 49). Women with the luminal A subtype of breast tumors respond well to therapy and have a good prognosis, whereas the outcome is poor for women with the luminal B subtype of tumors, nearly as poor as that seen in the case of ERnegative tumors. Our lab recently identified a gene signature synergistically upregulated by cross talk between ER and NF-B that is highly associated with luminal B but not luminal A-type tumors (16). This signature is enriched for cell survival genes, including the cellular inhibitor of apoptosis gene, cIAP2, which is also known as BIRC3. We have previously shown that BIRC3 is upregulated by estradiol (E2) and the proinflammatory cytokine tumor necrosis factor alpha (TNF-␣) in a number of ER-positive but not ER-negative cell lines. Using chemical inhibitors and a small interfering RNA (siRNA) approach, our lab has further demonstrated that BIRC3 plays an important role in promoting estrogendependent breast cancer cell survival and protecting against TNF-␣-induced cell death (51). Understanding the mechanism by which BIRC3 is upregulated by cross talk between ER and NF-B is therefore of clinical relevance.The ER subtypes, ER␣ and ER, are ligand-dependent transcription factors that interact with DNA and control transcription of ER target genes in resp...
FSH is a potent enhancer of IGF-2 expression in human granulosa cells. In return, IGF-2 activation of the IGF-1R and AKT is required for FSH to stimulate CYP19A1 expression and proliferation of granulosa cells. These findings suggest a positive loop interaction between FSH and IGF-2 that is critical for human granulosa cell proliferation and differentiation.
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