Increased, Ductal Hyperplasia leads to N/A, Breast Cancer

High. Carcinogenic agents increase proliferation and hyperplasia as well as tumors. Proliferation and hyperplasia appears prior to or at the same time as tumors, grow into carcinomas, and are more effective at forming mammary tumors than non-proliferating tissue. Disruption of proliferation is associated with decreased tumor growth, and tumor resistant rats do not show proliferation. However, the discrepancy between the non-linear proliferative and linear mammary tumor response to carcinogen dose coupled with evidence of independent occurrences of proliferation and tumorigenesis suggests that while proliferation and hyperplasia likely promote carcinogenesis, additional factors also contribute.

Factors that increase proliferation or hyperplasia also increase tumors. Proliferative epithelial cells, nodules and hyperplasia appear in mammary gland of rats and mice after exposure to chemical carcinogens (Beuving, Bern et al. 1967; Beuving, Faulkin et al. 1967; Russo, Saby et al. 1977; Purnell 1980) and ionizing radiation (Faulkin, Shellabarger et al. 1967; Ullrich and Preston 1991; Imaoka, Nishimura et al. 2006; Nguyen, Oketch-Rabah et al. 2011; Snijders, Marchetti et al. 2012; Suman, Johnson et al. 2012; Tang, Fernandez-Garcia et al. 2014). A subpopulation of post-senescent epithelial cells also proliferate following IR in vitro (Mukhopadhyay, Costes et al. 2010).

Proliferation and hyperplasia precede or are detected at the same time as tumors (Beuving, Bern et al. 1967; Beuving, Faulkin et al. 1967; Faulkin, Shellabarger et al. 1967; Haslam and Bern 1977; Russo, Saby et al. 1977; Purnell 1980; Imaoka, Nishimura et al. 2005; Imaoka, Nishimura et al. 2006) and form tumors more effectively than non-proliferating tissue (Deome, Faulkin et al. 1959; Beuving 1968; Rivera, Hill et al. 1981). Adenocarcinomas appear to form from terminal end bud hyperplasia in rats (Haslam and Bern 1977; Russo, Saby et al. 1977; Purnell 1980), similar to the origin of many breast cancers for humans and for some mice after IR (Medina and Thompson 2000).

Interrupting or preventing proliferation or hyperplasia reduces the incidence (or growth) of tumors. Disruption of proliferation or hyperplasia formation disrupts tumor growth (Luo, Fan et al. 2009; Connelly, Barham et al. 2011; Tang, Fernandez-Garcia et al. 2014). Similarly, ACI rats exhibit no proliferation or hyperplasia following IR and are resistant to tumors following IR (Shellabarger, Stone et al. 1976; Kutanzi, Koturbash et al. 2010).

In the relatively small number of studies that examine the dose-dependence of proliferation and hyperplasia in models of carcinogenesis, proliferation does not appear to increase linearly with dose (Han, Chen et al. 2010; Mukhopadhyay, Costes et al. 2010; Nguyen, Oketch-Rabah et al. 2011; Tang, Fernandez-Garcia et al. 2014) while tumor formation and carcinogenesis does increase linearly with dose.

Some studies report carcinogenesis in the absence of hyperplasia (Middleton 1965; Sinha and Dao 1974) and others do not find increased tumorigenesis from transplanted hyperplasia (Haslam and Bern 1977; Sinha and Dao 1977). In Copenhagen rats resistant to tumors from MNU treatment, hyperplasia appear after MNU treatment but do not progress into carcinomas in situ, instead disappearing over time (Korkola and Archer 1999). Similarly, Fisher rats are less sensitive to tumor induction by DMBA, and hyperplasia from these rats do not go on to form tumors when transplanted (Beuving, Bern et al. 1967).