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Background: Fascin is a pro-metastasis actin bundling protein overexpressed in basal-like breast cancer. Results: GATA3 abrogates TGF␤ and Smad4-mediated fascin overexpression by abolishing the binding of Smad4 to fascin promoter. Conclusion: GATA3 is a novel suppressor of the canonical TGF␤-Smad signaling pathway. Significance: These findings provide mechanistic insight into how TGF␤-mediated invasion and metastasis are differentially regulated in different subgroups of breast cancer.

Cigarette smoking is the major risk factor for non-small cell lung cancer (NSCLC), which accounts for 80% of all lung cancers. Nicotine, the addictive component of tobacco smoke, can induce proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), angiogenesis, and survival in NSCLC cell lines, as well as growth and metastasis of NSCLC in mice. This nicotine-mediated tumor progression is facilitated through activation of nicotinic acetylcholine receptors (nAChRs), specifically the α7 subunit; however, how the α7 nAChR gene is regulated in lung adenocarcinoma is not fully clear. Here we demonstrate that the α7 nAChR gene promoter is differentially regulated by E2F and STAT transcription factors through a competitive interplay; E2F1 induces the promoter, while STAT transcription factors repress it by binding to an overlapping site at a region -294 through -463bp upstream of the transcription start site. Treatment of cells with nicotine induced the mRNA and protein levels of α7 nAChR; this could be abrogated by treatment with inhibitors targeting Src, PI3K, MEK, α7 nAChR, CDK4/6 or a disruptor of the Rb-Raf-1 interaction. Further, nicotine–mediated induction of α7 nAChR was reduced when E2F1 was depleted and in contrast elevated when STAT1 was depleted by siRNAs. Interestingly, extracts from e-cigarettes, which have recently emerged as healthier alternatives to traditional cigarette smoking, can also induce α7 nAChR expression in a manner similar to nicotine. These results suggest an autoregulatory feed-forward loop that induces the levels of α7 nAChR upon exposure to nicotine, which enhances the strength of the signal. It can be imagined that such an induction of α7 nAChR contributes to the tumor-promoting functions of nicotine.

Regulators of the cell cycle machinery play a major role in modulating a variety of cellular phenomena including proliferation, quiescence, differentiation, senescence and apoptosis. Studies in the past decade have clearly established a role for the retinoblastoma tumor suppressor protein, Rb, and its primary downstream target E2F1, in the above processes. While the role of the Rb protein in the regulation of cell cycle progression has been analyzed in great detail, its potential roles in apoptosis as well as senescence are relatively less studied. It has become increasingly clear that the anti-apoptotic functions of Rb contribute significantly to the genesis and progression of tumors. This is especially relevant in neuronal systems, since terminally differentiated neurons do not proliferate; therefore the normal anti-proliferative functions of Rb in neurons are not very dominant. This chapter describes the current thoughts on the role of Rb function in the apoptosis and senescence of cells, both of neuronal and non-neuronal origin. Recent studies have also addressed how Rb function is differentially modulated by proliferative and apoptotic signals received at the cell surface, though both lead to Rb inactivation. The contribution of Rb to inducing cellular senescence has been long recognized, but the underlying molecular mechanisms are being elucidated only recently; the contribution of this function of Rb to tumor suppression remains to be understood in detail. It can be expected that an understanding of Rb function in cellular apoptosis and senescence will enhance our ability to develop novel agents and strategies to combat cancer.

Background Greater ovulatory years is associated with increased ovarian cancer risk. Although ovulation leads to an acute pro-inflammatory local environment, how long-term exposure to ovulation impacts ovarian carcinogenesis is not fully understood. Thus, we examined the association between gene expression profiles of ovarian tumors and lifetime ovulatory years to enhance understanding of associated biological pathways. Methods RNA sequencing data was generated on 234 invasive ovarian cancer tumors that were high-grade serous, poorly differentiated, or high-grade endometrioid from the Nurses’ Health Study (NHS), NHSII, and the New England Case Control Study. We used linear regression to identify differentially expressed genes by estimated ovulatory years, adjusted for birth decade and cohort, overall and stratified by menopausal status at diagnosis. We used false discovery rates (FDR) to account for multiple testing. Gene set enrichment analysis (GSEA) with Cancer Hallmarks, KEGG, and Reactome databases was used to identify biological pathways associated with ovulatory years. Results No individual genes were significantly differentially expressed by ovulatory years (FDR > 0.19). However, GSEA identified several pathways that were significantly associated with ovulatory years, including downregulation of pathways related to inflammation and proliferation (FDR < 1.0 × 10–5). Greater ovulatory years were more strongly associated with downregulation of genes related to proliferation (e.g., E2F targets, FDR = 1.53 × 10–24; G2M checkpoints, FDR = 3.50 × 10–22) among premenopausal versus postmenopausal women at diagnosis. The association of greater ovulatory years with downregulation of genes involved in inflammatory response such as interferon gamma response pathways (FDR = 7.81 × 10–17) was stronger in postmenopausal women. Conclusions Our results provide novel insight into the biological pathways that link ovulatory years to ovarian carcinogenesis, which may lead to development of targeted prevention strategies for ovarian cancer.