Increase, Mutations leads to Increase, Cell Proliferation (Epithelial Cells)

Mutations are clearly not the only events driving proliferation in mammary gland, particularly in female mammary glands after exposure to a stressor like ionizing radiation where proliferation varies with age and microenvironment (Tang, Fernandez-Garcia et al. 2014). In mammary tissue, stromal state strongly influences the proliferative and metastatic nature of epithelial cells, and mutated epithelial cells alone appear to be insufficient for tumor growth.  Stroma exposed to carcinogens can make transplanted unexposed epithelial cells tumorigenic in rats (Maffini, Soto et al. 2004) and transplanted p53 mutant epithelial cells tumorigenic in BALB/c mice (Barcellos-Hoff and Ravani 2000), while neither epithelia exposed to carcinogens nor p53 mutant cells are tumorigenic when transplanted into unexposed animals (Barcellos-Hoff and Ravani 2000; Maffini, Soto et al. 2004). Similarly, post-lactational stroma can make tumor cells more invasive and metastatic than nulliparous stroma (McDaniel, Rumer et al. 2006), and younger and nulliparous stroma makes tumor cells proliferate more than older and multiparous stroma (Maffini, Calabro et al. 2005). Even proliferating tissue and tumors can regress (Haslam and Bern 1977; Purnell 1980), suggesting that proliferation is insufficient for carcinogenesis in some cases.

While mutations increase linearly in response to ionizing radiation or carcinogens, proliferation (or proliferation of stem cell populations) apparently does not (Beuving, Bern et al. 1967; Mukhopadhyay, Costes et al. 2010; Nguyen, Oketch-Rabah et al. 2011; Tang, Fernandez-Garcia et al. 2014). Because we expect only a subset of mutations to affect cell-cycle or proliferation-related genes and because most cells require multiple mutations for proliferation to commence, only a very small number of cells would be expected to proliferate in response to mutation. It is therefore possible that the proliferation typically observed is actually due to a separate mechanism such as the self-renewal of stem-like or senescent-resistant cells and that a delayed mutation-based proliferation is not being measured.

Proliferation increases the likelihood that existing DNA damage will result in mutation and creates new mutations through errors in replication.

It is generally accepted that proliferation increases the risk of mutation and cancer (Preston-Martin, Pike et al. 1990). DNA damage that has not been completely or correctly repaired when a cell undergoes mitosis can be fixed in the genome permanently as a mutation, to be propagated to future daughter cells. Incomplete DNA repair can also cause additional DNA damage when encountered by replicative forks. Therefore, in the presence of any DNA damage (and there is a background rate of damage in addition to any other genotoxic stimuli) mutations will increase with cell division (Kiraly, Gong et al. 2015). Mutation-prone double strand breaks can also arise from replicative stress in hyperplastic cells including hyperplasia arising from excess growth factor stimulation (Gorgoulis, Vassiliou et al. 2005). This relationship between proliferation and mutation is thought to drive a significant portion of the risk of cancer from estrogen exposure since breast cells proliferate in response to estrogen or estrogen plus progesterone and risk increases with cumulative estrogen exposure (Preston-Martin, Pike et al. 1990).

Not all proliferating tissue shows replicative stress and DSBs - tissue with a naturally high proliferative index like colon cells don’t show any sign of damage (Halazonetis, Gorgoulis et al. 2008). Additional factors are therefore required beyond replication for damage and mutation from replicative stress, but replication is essential for the expression of these factors.

Gorgoulis, V. G., L. V. Vassiliou, et al. (2005). "Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions." Nature 434(7035): 907-913.

Halazonetis, T. D., V. G. Gorgoulis, et al. (2008). "An oncogene-induced DNA damage model for cancer development." Science 319(5868): 1352-1355.

Kiraly, O., G. Gong, et al. (2015). "Inflammation-induced cell proliferation potentiates DNA damage-induced mutations in vivo." PLoS Genet 11(2): e1004901.

Preston-Martin, S., M. C. Pike, et al. (1990). "Increased cell division as a cause of human cancer." Cancer Res 50(23): 7415-7421.