Introduction
The majority of breast cancers (BCs) are characterized by the expression of estrogen receptor alpha (ERα+). ERα acts as ligand-dependent transcription factor for genes associated with ...cell survival, proliferation, and tumor growth. Thus, blocking the estrogen agonist effect on ERα is the main strategy in the treatment of ERα+ BCs. However, despite the development of targeted anti-estrogen therapies for ER+ BC, around 30–50% of early breast cancer patients will relapse. Acquired resistance to endocrine therapy is a great challenge in ER+ BC patient treatment.
Discussion
Anti-estrogen resistance is a consequence of molecular changes, which allow for tumor growth irrespective of estrogen presence. Those changes may be associated with ERα modifications either at the genetic, regulatory or protein level. Additionally, the activation of alternate growth pathways and/or cell survival mechanisms can lead to estrogen-independence and endocrine resistance.
Conclusion
This comprehensive review summarizes molecular mechanisms associated with resistance to anti-estrogen therapy, focusing on genetic alterations, stress responses, cell survival mechanisms, and cell reprogramming.
The purpose of the present study was to characterise patients with breast cancer (BC) and
mutation (age ≥ 50 years) according to their clinicopathological factors or family history. Patients aged ≥ ...50 years were compared with the control group and with
mutation carriers aged < 50 years.
Prognostic factors were analysed in patients with BC with confirmed
c.3016_3017insC (
= 150) mutations. The control group was selected from patients with BC without mutations (
= 376).
There were significant differences between
-mutation carriers and the control group aged ≥ 50 years, according to HER2 overexpression (
= 0.0001), ER (-) (
= 0.007), PR (-) (
= 0.003), T1-T2 (
= 0.011), and G3
= 0.036). Similarly, significant differences were observed between
-mutation carriers and the control group aged < 50 years, according to HER2 overexpression (
= 0.0001), ER (-) (
= 0.049), and N (+) (
= 0.038). In patients aged ≥ 50 years, family history of cancer, including BC, was observed more often in
-mutation carriers compared with the control group of patients (OR = 1.66;
= 0.072, for BC in family history: OR = 2.65;
= 0.002).
-mutation carriers aged ≥ 50 years had significantly less frequent G3 (
= 0.004) and HER2 overexpression (
= 0.043) compared with patients with
mutation aged < 50 years.
The presence of the
mutation is not only characteristic of younger patients but also in patients > 50 years of age. In
-mutation carriers aged ≥ 50 years, the presence of larger tumour size, G3, or HER2 overexpression were lower compared with younger patients with
mutation.
Aberrant expression of DNA polymerase β, a key enzyme involved in base excision repair, leads to genetic instability and carcinogenesis. Pol β expression has been previously shown to be regulated at ...the level of transcription, but there is also evidence of post-transcriptional regulation, since rat transcripts undergo alternative polyadenylation, and the resulting 3′UTR contain at least one regulatory element. Data presented here indicate that RNA of the short 3′UTR folds to form a strong secondary structure (hairpin). Its regulatory role was established utilizing a luciferase-based reporter system. Further studies led to the identification of a protein factor, which binds to this element—the anti-apoptotic, cytoskeleton-related protein Hax-1. The results of in vitro binding analysis indicate that the formation of the RNA–protein complex is significantly impaired by disruption of the hairpin motif. We demonstrate that Hax-1 binds to Pol β mRNA exclusively in the form of a dimer. Biochemical analysis revealed the presence of Hax-1 in mitochondria, but also in the nuclear matrix, which, along with its transcript-binding properties, suggests that Hax-1 plays a role in post-transcriptional regulation of expression of Pol β.
HS-1-associated protein X-1 (HAX-1) was identified more than 10 years ago as a novel protein with ubiquitous tissue expression and a predominantly mitochondrial localization at the subcellular level. ...Recent studies have shown that homozygous mutations in the
HAX1 gene are associated with autosomal recessive forms of severe congenital neutropenia (also known as Kostmann disease), and results from studies in mice and men are beginning to unravel a prominent role for HAX-1 in apoptosis signaling not only in the hematopoietic compartment, but also in the central nervous system. Moreover, several different cellular and viral binding partners of HAX-1 have been identified thus pointing toward a complex and multifunctional role of this protein. HAX-1 has also been shown to bind to the 3′ untranslated regions of certain mRNAs and could therefore contribute to the regulation of transport and/or stability of such transcripts. The present review discusses the emerging and divergent roles of HAX-1, including its involvement in cell migration, apoptosis signaling, and mRNA surveillance. The importance of HAX-1 in human disease is also highlighted and outstanding questions that remain to be addressed are identified.
The nuclear receptor coactivator 3 (NCOA3, also known as AIB1) is a coactivator of nuclear receptors like the estrogen receptor. NCOA3 is overexpressed in approximately 60% of primary human breast ...tumors, and high levels of NCOA3 expression are associated with tamoxifen resistance and worse survival rate. In contrast, NCOA3 deficiency suppresses v-Ha-ras-induced breast cancer initiation and progression in mice. Here, we analyzed the influence of NCOA3 coding single nucleotide polymorphisms on breast cancer risk by performing a case-control study using a German and a Polish study population and identified an association between NCOA3 polymorphisms and breast cancer. A joint analysis of the German and the Polish study population revealed a significant protective effect for the 1758G>C (Q586H) and 2880A>G (T960T) variants. In addition, haplotype analysis showed a protective effect of the 1758C-2880A and 1758G-2880G haplotypes (odds ratio 0.79; 95% confidence interval, 0.67-0.93; P = 0.004). Because of the impact of NCOA3 in antiestrogen therapy resistance, these polymorphisms might also influence therapy outcome in breast cancer.
Hax-1 protein, which has been studied in mice and humans, shows a potent anti-apoptotic activity and is involved in regulation of cell motility. Cloning of the rat
Hax-1 cDNA has revealed seven ...alternative transcripts, which differ mostly in their 5′ region. Alternative splicing concerns exon 1, skipped in 5 transcripts, intron 1 which is partially retained in these transcripts, exon 2, which can be partially skipped, and intron 2, retained in one variant. The existence of different splicing variants was confirmed by exon-junction-specific RT-PCR and RNase protection assay. Analysis of expression indicates that overall
Hax-1 mRNA level is relatively low in most tissues and very high in testes, and that the expression pattern of the variants is similar in different tissues. Presence of different transcripts implies the existence of several protein isoforms, with three putative start codons. The existence of at least three protein isoforms was confirmed by Western blot. Interestingly, high mRNA level in testes does not translate into high protein level, suggesting the existence of tissue-specific translational regulation or regulated protein degradation.
The differences in patients' response to the same medication, toxicity included, are one of the major problems in breast cancer treatment. Chemotherapy toxicity makes a significant clinical problem ...due to decreased quality of life, prolongation of treatment and reinforcement of negative emotions associated with therapy. In this study we evaluated the genetic and clinical risk factors of FAC chemotherapy-related toxicities in the group of 324 breast cancer patients. Selected genes and their polymorphisms were involved in FAC drugs transport (
), metabolism (
), DNA damage recognition, repair and cell cycle control (
). The multifactorial risk models that combine genetic risk modifiers and clinical characteristics were constructed for 12 toxic symptoms. The majority of toxicities was dependent on the modifications in components of more than one pathway of FAC drugs, while the impact level of clinical factors was comparable to the genetic ones. For the carriers of multiple high risk factors the chance of developing given symptom was significantly elevated which proved the factor-dosage effect. We found the strongest associations between concurrent presence of clinical factors - overall and recurrent anemia, nephrotoxicity and early nausea and genetic polymorphisms in genes responsible for DNA repair, drugs metabolism and transport pathways. These results indicate the possibility of selection of the patients with expected high tolerance to FAC treatment and consequently with high chance of chemotherapy completion without the dose reduction, treatment delays and decline in the quality of life.
The presence of BRCA1 mutations is associated with an increased risk of breast and ovarian cancer. The present study compared clinicopathological characteristics and overall survival (OS) of ...hereditary and sporadic breast cancer. Using data collected from a previous study conducted between 2007-2016 at the Maria Skłodowska Curie Cancer Center and Institute of Oncology (Gliwice, Poland), the prognostic factors and survival in 60 breast cancer mutation carriers were analyzed. A control group was selected from the breast cancer patients without BRCA mutations (n=386). BRCA mutation carriers had significantly worse survival when compared with non-carriers (P=0.017). The 10-year OS rate was 78.0% for all analyzed groups: 65.9% for BRCA mutation carriers and 81.1% for non-carriers. In the univariate analyses, BRCA mutation carriers had a significantly higher risk of mortality in comparison to non-carriers hazard ratio (HR)=1.87; 95% confidence interval (CI) 1.08-3.25. Increased tumor size (HR=3.64), lymph node metastases (HR=2.45) and higher histological grade (HR=2.84) were significant factors for worse OS. Positive estrogen receptor status was associated with a better OS (HR=0.49, P=0.022). Age ≤40 years (HR=0.48, P=0.081) was an insignificantly favorable factor. The 10-year survival rate was significantly decreased in patients with BRCA1 mutation. Therefore, negative factors for OS in mutation carriers included lymph nodes metastases, negative steroid receptor status and increased tumor size.
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