Contrasting epistatic interactions between rat quantitative trait loci controlling mammary cancer development.
We previously defined quantitative trait loci (QTLs) that control susceptibility to 7,12-dimethylbenz(alpha)anthracene-induced mammary carcinoma in SPRD-Cu3 (susceptible) and WKY (resistant) rats. Two of these QTLs, assigned to chromosomes (Chr) 10 and 18, control tumor growth rate and invasiveness. In this study we characterized a congenic strain in which a large segment of WKY Chr 10 was introduced in the SPRD-Cu3 genetic background and demonstrated that this chromosome segment controls this tumor trait. The WKY allele at this QTL (Mcsta1) reduces the growth rate of the fastest growing tumors by 26%. We also previously showed that two SPRD-Cu3-WKY congenic strains containing a WKY chromosome segment derived either from Chr 5 or from Chr 18 exhibit a reduction in tumor multiplicity (QTLs Msctm1 and Mcstm2, respectively) (with no reduction in tumor growth rate in the Chr 18 congenic). In this study we generated a double congenic strain, which contains the two WKY differential segments from Chr 5 and 18, to determine how these two segments interact with one another. Interestingly, two types of epistatic interactions were found: no additive effect was seen with respect to tumor multiplicity, while a reduction in tumor growth rate was observed. It thus appears that WKY alleles located on Chr 5 and Chr 8 interact epistatically in a contrasting manner to modulate tumor multiplicity (in a nonadditive manner) and growth rate (in a synergic manner). Tumor growth rate is thus influenced by two QTLs, on Chr 10 (Mcsta1) and on Chr 18 (Mcsta2), the action of the latter being dependent on the presence of the Chr5 QTL (Mcstm1). The expression level of positional and functional candidate genes was also analyzed. On Chr 5, Pla2g2a is subject to a syntenic control while expression of the Tp53 (Chr 10) and Pmai1/Noxa (Chr 18) genes appears to be controlled by several mammary cancer resistance QTLs.
Piessevaux
Géraldine
G
Institut de Biologie et de Médecine Moléculaires, Université Libre de Bruxelles, 12, 6041, Gosselies, Belgium.
Lella
Virginie
V
Rivière
Michèle
M
Stieber
Daniel
D
Drèze
Pierre
P
Szpirer
Josiane
J
Szpirer
Claude
C
D000818:Animals; D020296:Animals, Congenic; D001483:Base Sequence; D002874:Chromosome Mapping; D004843:Epistasis, Genetic / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D016158:Genes, p53 / Q000502:physiology; D020022:Genetic Predisposition to Disease; D054501:Group II Phospholipases A2 / Q000235:genetics; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000235:genetics*; D008969:Molecular Sequence Data; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D040641:Quantitative Trait Loci; D051381:Rats; D011919:Rats, Inbred Strains; D011921:Rats, Inbred WKY; D012689:Sequence Homology, Nucleic Acid
C539472:Pmaip1 protein, rat; D019253:Proto-Oncogene Proteins c-bcl-2; D054501:Group II Phospholipases A2; C516289:Pla2g2a protein, rat