Role of CCND1 and C-MYC oncogenes in metastatic breast cancer patients treated by herceptin

Abstract

Breast cancer consists of multiple diff erent molecular subtypes and diff erent biological processes, and consequently diff erent molecular markers are associated with prognosis and chemotherapy sensitivity in the distinct disease subsets [1]. A large number of biological processes including cell cycle regulation, DNA replication, mitotic spindle checkpoint, and p53 function are strongly prognostic in ER + cancers but not among ERcancers [2,3]. Interestingly, the number of biological pathways, and therefore genes, that are associated with prognosis or treatment sensitivity are substantially larger and more consistent in ER + cancers than among ERtumors [1,4]. This implies that it is easier to discover prognostic and predictive markers for ER + than for ERcancers. In ERcancers, the single most consistent, but still modestly accurate, good prognostic predictor is the presence of immune cell infi ltration [5]. Immune cell signatures are also associated with more favorable prognosis in highly proliferative ER + cancers but not in ER + cancers with low proliferation [6]. It is also increasingly clear that the same molecular marker can be associated with several diff erent outcome endpoints in various and often opposing manners. For example, high Ki67 expression is predictive of worse prognosis in the absence of any systemic therapy in ER + cancers, but at the same time it is also predictive of higher sensitivity to chemotherapy. Similar opposing bidirectional associations with treatment response and prognosis exist for many other markers including histologic grade, Tau protein expression and almost all prognostic gene signatures [7]. It is important to be aware of these complex multi-directional interactions between molecular markers and various clinical endpoints that may also vary from breast cancer subtype to subtype. Ignoring these potential marker-disease subset-outcome interactions can lead to contradictory and confusing results across studies (due to diff erences in patient composition and heterogeneity of therapy between studies) and may also lead to the discovery of biomarkers that are clinically less useful (because of unrecognized subtype-restricted performance) [8,9]. References 1. Iwamoto T, Bianchini G, Booser D, et al.: Gene pathways associated with prognosis and chemotherapy sensitivity in molecular subtypes of breast cancer.

Integrated MicroRNA and mRNA Signatures Associated with Survival in Triple Negative Breast Cancer

“…CCND1 gene amplification has been related to poor disease outcome in ER-positive cancers, but other studies have correlated cyclin D1 protein expression with both better and worse prognosis. It is known that amplifications of CCND1 and MYC frequently occur together in breast cancer [22]; accordingly, we observed its down-regulation coupled with MYC down-regulation (logFC −1.2). In the normal vs mets comparison, the expression trend for 2 genes was intriguing: up-regulation of CXCL9 (logFC 1.7) and down-regulation of IL8 (logFC −0.8).…”

Diverse Developmental Disorders from The One Ring: Distinct Molecular Pathways Underlie the Cohesinopathies

“…Mice heterozygous for a Rad21 null mutation are hypersensitive to IR, and exhibit problems with integrity and maintenance of the gastrointestinal tract and hematopoietic system post-irradiation (Xu et al, 2010). In humans, patients with RAD21 mutations also have impaired DNA damage repair (Deardorff et al, 2012b), and knock down of RAD21 sensitizes breast cancer cells to chemical agents that damage DNA (Atienza et al, 2005; Xu et al, 2011). Therefore, full dosage and function of the Rad21 gene is crucial for DNA damage repair.…”