Locus of fragility in robust breast cancer system

Abstract

Functional heterogeneous redundancy of breast cancer makes this tumor to be robust. Signaling mechanisms which control cancer responses are crucial for controlling robustness. Identification of locus of fragility in cancer represents basic mechanism to target robustness. The goal of this prospect is to present locus of fragility in breast cancer robust system, and how disruption of this locus induces failure of robustness. My recent research show, that locus of fragility in breast cancer cells is suppression of nitric oxide (NO). When it was targeted, dynamics of cancer to generate robustness failed that it blocked cancer cell proliferation dependent on the NO/Rb pathway, blocked cell migration and angiogenesis dependent on the VEGF/PI3K/AKT/NO/ICAM-1 pathway, and induced breast cancer cell apoptosis through the NO/ROCK/FOXO3a signaling pathway. This tiny and trivial perturbation in breast cancer cells such as suppression of NO represents locus of fragility (weakness) and new approach for breast cancer chemotherapy.

AKT as Locus of Hydrogen Bond Network in Cancer

“…Such energetic process is initiated by the hyperphosphorylated and hyperactivated AKT locus from the hypoxic microenvironment by the positive feedback loops which interconvert the AKT protein to a folded state (active state), a conformational change of the protein ready for interaction of the active sites, thus, generating hydrogen bond network ( Fig. 1) and activating an entropy/enthalpy process for the ATP generation, the energy used for the interconversion of the AKT protein [Radisavljevic, 2004a,b, 2008, 2013a,b,c, 2015a,b, 2016, Pontiggia et al, 2015. Binding free energy and entropy/enthalpy are two energies necessary for the maintenance of malignant phenotype.…”

“…Proton beam methodology has advantages over conventionally use of X-ray techniques in pediatric cancers because there is no development of late secondary cancers like after X-ray radiotherapy [Brahme, 2000;Levin et al, 2005;Loeffler and Durante, 2013]. Pentose cycle and tricarboxylic acid (TCA) cycle (citric acid cycle or Krebs cycle) are essential in generating cancer energy-ATP and NADH, an element for ATP production [Radisavljevic, 2015a] and generation of deuterium by the activity of fumarate hydratase, a metabolic regulator in TCA cycle which controls cell proliferation [Tong et al, 2011; Guitart et al, 2017] through the AKT locus [Radisavljevic et al, 2000;Radisavljevic, 2004a Radisavljevic, ,b, 2008Radisavljevic, , 2013a Radisavljevic, ,b,c, 2015a Radisavljevic, ,b, 2016. Fumarate hydratase is the TCA cycle enzyme and tumor suppressor, which mutation causes development of renal cell carcinoma, leiomyoma, paraganglioma, and pheochromocytoma [Hoekstra et al, 2015].…”

“…Hydrogen is essential element in cancer signaling. AKT as a locus of cancer robustness and fragility [Radisavljevic, 2004a[Radisavljevic, , b, 2008[Radisavljevic, , 2013a[Radisavljevic, ,b,c, 2015a[Radisavljevic, ,b, 2016 functions trough the hydrogen bonds. Targeting hydrogen bond as a specific element in signaling could be achieved by the hydrogen balance change which will cause complete failure of cancer robustness and complexity.…”

“…Hydrogen bond network conforms entropy/enthalpy, energy in the system and its deregulation causes entropy decrease and deregulation of the entire cancer system [Radisavljevic, 2015a]. If recharge of signals continues from a cancer hypoxic microenvironment, entropy/enthalpy generation persists, and uses for cell proliferation, cell migration, angiogenesis, and maintenance of the cancer complex and robust system [Radisavljevic, 2003[Radisavljevic, , 2004a[Radisavljevic, ,b, 2008[Radisavljevic, , 2013a[Radisavljevic, ,b,c, 2015a[Radisavljevic, ,b, 2016.Targeting hydrogen bond networks by hydrogen balance change alone or in combination with the redox balance change is the best way to target cancer robustness and complexity through the AKT locus [Radisavljevic, 2008]. Redox balance change is the super master regulator of the AKT locus [Radisavljevic, 2004a[Radisavljevic, ,b, 2008[Radisavljevic, , 2013a[Radisavljevic, ,b,c, 2015a[Radisavljevic, ,b, 2016, which disrupts hydrogen bond networks [Kostic et al, 2002;Santoni et al, 2004;Keough et al, 2013] causing failure of the cancer robustness.…”

“…Targeting hydrogen bond as a specific element in signaling could be achieved by the hydrogen balance change which will cause complete failure of cancer robustness and complexity. Network of the complex signaling pathways for cancer cell proliferation through the Rb/AKT/NO pathway [Radisavljevic, 2004b] and the PI3 K/AKT/mTOR/ RAN pathway [Radisavljevic and Gonzalez-Flecha, 2004], cell migration through the VEGF/AKT/ICAM1 pathway [Radisavljevic et al, 2000] are achieved by the hydrogen bonds at active sites [Ishikita and Saito, 2013;Liu et al, 2015] of the AKT locus [Radisavljevic et al, 2000;Radisavljevic, 2004aRadisavljevic, ,b, 2008Radisavljevic, , 2013aRadisavljevic, ,b,c, 2015aRadisavljevic, ,b, 2016Radisavljevic and Gonzalez-Flecha, 2004].…”