Does DNA ploidy and synthesis phase dynamic accentuate the predictive power of oestrogen and progesterone receptors in breast cancer progression and prognosis?

Oestrogen and progesterone receptors (ER and PR) are closely associated with breast cancer progression. In this review we identify and discuss cellular markers that can accentuate or complement the deployment of ER and PR for predicting prognosis. The focus is on aneuploidy and DNA ploidy which appear to be significant independent predictors of overall survival in many forms of cancer. Their importance in cancer development and progression flows from their origin in the inherent genetic instability. Genetic instability of chromosomes is seen as aneuploidy, chromosomal deletions, translocations and sister-chromatid recombination, and at the DNA level as altered DNA repair, gene amplification and deletion and point mutations. Microsatellite loci of repetitive nucleotide sequences are inherently unstable. Microsatellite instability is characterised by the loss of DNA mismatch repair activity leading to a hypermutable phenotype. Chromosome abnormalities result from the deregulation of cell cycle and immune checkpoint regulators. Failure of the DNA mismatch repair pathway could be one of the reasons for their incidence, although the available evidence is not unequivocal. Some tumours such as the colorectal carcinomas do not show an indisputable relationship between aneuploidy and microsatellite instability or mismatch repair deficiency. Epithelial mesenchymal transition (EMT) plays a crucial role in cancer biology. EMT is associated with the emergence and maintenance of cancer stem cells (CSC). Polyploidy and aneuploidy appear as a staging post to the formation of CSCs together with parallel activation of EMT. Chromosomal alterations may occur concomitantly with EMT as well as with the reverse process of mesenchymal epithelial transformation. Genetic profiling has revealed significant information concerning the abnormal growth kinetics of cancer cells. The DNA ploidy pattern is reflected in the polyploid and aneuploid states, aberrant gene amplification and expression and enlarged S-phase fraction. Aneuploidy may be a consequence of cells entering the S-phase of the cell Oestrogen and progesterone receptors in breast cancer Atlas Genet Cytogenet Oncol Haematol. 2018; 22(9) 408 cycle prematurely. DNA ploidy is also associated with aberrant expression of growth factor and hormone receptors. The DNA indices and the synthesis phase fraction (SPF) have been studied extensively in relation to tumour progression. The question we pose here is whether they enhance or counteract the function of ER/PR. Could they serve as complementary factors to predict prognosis of breast cancer. The expression of these cellular markers is quantified here by image cytometry (ICM) and the accrued data have been analysed by using binomial regression algorithm and the fuzzy K-Nearest Neighbour (FK-NN) classifier to see whether these cellular markers aid the prediction of nodal status and survival of breast cancer patients. The FK-NN analyses have revealed high prediction rates for both nodal involvement and 5-year survival. The FK-NN appears much superior in performance than techniques of logistic regression and multilayer feed-forward backpropagation (MLFFBPNN) the artificial neural network tool. A wide spectrum of evidence is presented here which supports the view that DNA ploidy and SPF acting as complementary factors accentuate the predictive power of ER/PR of breast cancer progression and provides credibility that they could deliver a more reliable prognostic model to assist in patient management.