Linking DNA Damage and Hormone Signaling Pathways in Cancer

Abstract

DNA damage response and repair (DDR) is a tightly controlled process that serves as a barrier to tumorigenesis. Consequently, DDR is frequently altered in human malignancy, and can be exploited for therapeutic gain either through molecularly targeted therapies, or as a consequence of therapeutic agents that induce genotoxic stress. In select tumor types, steroid hormones and cognate receptors serve as major drivers of tumor development/progression, and as such are frequently targets of therapeutic intervention. Recent evidence suggests the existence of crosstalk mechanisms linking the DDR machinery and hormone signaling pathways that cooperate to influence both cancer progression and therapeutic response. These underlying mechanisms and their implications for cancer management will be discussed.

Exploiting AR-Regulated Drug Transport to Induce Sensitivity to the Survivin Inhibitor YM155

“…Modest DNA-damage (γH2AX) was observed at the higher dose of YM155 with R1881 (FIG 2A). Reductions in γH2AX and cleaved PARP1 were observed in AR-suppressed cells in the control and low-dose YM155 groups, consistent with reduced replicative stress(46) and DNA-repair supportive effects of AR signaling(47) (FIG 2A). Additionally, there was no change in levels of autophagy (as measured by Beclin and AT5 levels) and negligible changes in apoptosis (as measured by cleaved-Caspase3 and PARP1) between the YM155 and control groups (FIG 2A).…”

Base Excision Repair Manipulation in Breast Carcinoma: A Prospective Avenue to Potentiate Genome Insulting Approach

“…Based on the previous genetic and pathological study, BRCA1-associated breast cancers are more likely to be estrogen (ER) and progesterone receptor (PgR) negative (~90%) matched with sporadic breast cancers (~30%). In contrast, the occurrence of ER and PgR for BRCA2-and BRCAX-associated cancers is not considerably different to sporadic cancers [1,3,6,34].…”

“…The reason behind the manipulation and subversion of DNA repair response on breast carcinoma is explored in the perspectives of hormonal signaling. There are sound evidences that certain steroid hormones alter the double strand break repair mediated by BRCA1 in case of hereditary type of breast cancer [34]. In BRCA1 and BRCA2 mutation associated cancer, overexpression of HER2 is seldom.…”

“…The well-crafted DNA damage repair machinery inside the cell is tightly regulated and according the division of work inside the cellular periphery, a specific family of repair team agent is recruited when particular lesion is sensed. Onset of carcinoma changes the DNA damage response which can be the cause of enhanced genotoxic stress which can be considered as targeted therapeutic agents [34].…”

The success of stem cell transplantations and the potential post-transplantation complications may be dependent, among other factors, on the capacity of the recipient and the transplanted cells to repair DNA damage

“…This was only the beginning of the studies on the role of IRC in human health and disease. It had later become clear that the capacity for DNA repair and management of genomic integrity in humans could have significant effects on the risk for development of many common diseases with late onset, such as diabetes and cancer (Roy et al 2007, Petkova et al 2011b, Schiewer and Knudsen 2016, cardiovascular disease (Chelenkova et al 2014, Wu andRoks 2014), neurodegenerative disease (Coppedè and Migliore 2015, Nayyar et al 2015); and that it could potentially reflect on the susceptibility for disease in different individuals, and at different ages (Cherdyntseva et al 2010, Petkova et al 2013 and the outcomes of different genotoxic treatments (Kan and Zhang 2015, Velic et al 2015, Petkova et al 2014b. DNA damage repair pathways began to be regarded as useful therapeutic targets in cancer therapy, , Khalil et al 2012b, Khalil et al 2012c, Gavande et al 2016.…”