Mammary cancer resistance and precocious mammary differentiation in the WKY rat: Identification of 2 quantitative trait loci

Abstract

The COP and WKY rat strains are resistant to mammary cancer. It has shown previously that upon chemical carcinogen treatment, COP females exhibit mammary preneoplastic lesions which disappear within a few weeks. We show here that in similar conditions, WKY females do not exhibit any visible preneoplastic lesions. WKY females are characterized by precocious mammary tissue differentiation, including active expression of the beta-casein gene in young virgin females. This trait might be critical in resistance to mammary carcinogenesis of WKY rats. To test this hypothesis, we took advantage of 2 congenic strains that contain a limited chromosome segment of WKY origin, derived either from chromosome 5 or from chromosome 18, introgressed in the susceptible genetic background (SPRD-Cu3). Each of these congenic strains has been shown to be partially resistant to chemically induced mammary carcinogenesis (reduction in tumour multiplicity with respect to the susceptible SPRD-Cu3 rats). We show here that these 2 congenic strains also exhibit precocious mammary differentiation, though to a lower extent than the WKY females. The conclusion of this study is thus 2-fold: (i) eradication of preneoplastic lesions is not a general phenomenon in mammary cancer resistance; (ii) the same segment of rat chromosomes 5 or 18 that controls mammary cancer resistance also contains a quantitative trait locus imposing precocious mammary differentiation. These 2 traits are thus associated, supporting the hypothesis that there might be a cause-effect relationship between precocious mammary differentiation and cancer resistance. ' 2007 Wiley-Liss, Inc.Key words: rat; mammary; cancer; differentiation; congenics Breast cancer is the most frequent malignancy diagnosed in women in the Western world. The disease affects around 10% of the women in this part of the globe. Although it is now known that breast cancer is a multi-factorial disease, with a polygenetic (including inherited familial predisposition) and environmental aetiology, no specific etiologic agent and no initiation mechanism have been identified yet. 1,2 Owing to the genetic heterogeneity of the human population, the genetic dissection of breast cancer susceptibility is very tenuous in human cohorts. It is then useful to dissect the resistance/susceptibility phenotype first in model organisms and later, translate the results into the human population by a comparative genomic approach.3-5 Rodents are particularly useful for the study of mammary cancer because rodent mammary neoplasms, and rat adenocarcinomas in particular are remarkably similar to those seen in the human condition. [6][7][8][9] There are several inbred rat strains that are highly susceptible or resistant to mammary cancer. The resistance phenotype is relevant to both spontaneous and induced tumours.10-12 One prominent cancer-inducing agent is the polycyclic aromatic chemical 7, 12-dimethylbenz[alpha]anthracene (DMBA) but several other chemicals, as well as estrogens and radiations, also exhibit mammary cancer inducing ...

Association Between Resistance to Mammary Cancer Development and Upregulation of DNA Damage Response Genes

“…We suggest that resistance of the WKY rats to mammary cancer is explained by their capacity to activate an early and robust DDR. This feature also explains our previous observation, namely that DMBA-treated WKY rats do not develop pre-neoplasic lesions [16].…”

“…We previously showed that precocious mammary differentiation also segregates with mammary cancer resistance in the congenic strains [16]. A critical feature of precocious mammary differentiation might thus be the ability of mammary cells to generate an efficient DDR, including upregulation of genes involved in this response.…”

“…Indeed, upon chemical carcinogen treatment, COP females exhibit mammary preneoplastic lesions which disappear after several weeks [32], a phenomenon which could be explained by a form of immune surveillance, while in the same circumstances, WKY females do not show any lesion [16]. These observations led us to hypothesize that in the WKY strain, DNA injury induces a prompt and efficient DDR leading to a robust anti-cancer barrier.…”

“…Several quantitative trait loci (QTLs) controlling susceptibility induced mammary cancer have been identified in the rat [for recent reviews, see 10,13]. We previously reported the identification of several loci controlling mammary cancer susceptibility, and more precisely controlling multiplicity of 7,12-dimethyl benz[a]anthracene (DMBA)-induced mammary tumours: QTLs were notably assigned to rat chro- [16,17]. DMBA is an indirect carcinogen, which has to be metabolised to generate mutations and tumorigenesis, notably through the formation of bulky DNA adducts [18].…”

“…Each of these congenic strains carries, on the SPRD-Cu3 genetic background, a WKY-derived chromosome segment (from chromosome 5 or from chromosome 18). These two congenic strains [SPRD-Cu3-Mcstm1 (in brief, C5.Mcstm1) and SPRD-Cu3-Mcstm2 (in brief, C18.Mcstm2)] exhibit a reduction of 65% and 33% in DMBA-induced tumour multipliciyty, respectively [16,17].…”