Pregnancy in the mature adult mouse does not alter the proportion of mammary epithelial stem/progenitor cells

Introduction In humans, an early full-term pregnancy reduces lifetime breast cancer risk by up to 50% whereas a later pregnancy (>35 years old) can increase lifetime risk. Several mechanisms have been suggested, including changes in levels of circulating hormones, changes in the way the breast responds to these hormones, changes in gene expression programmes which may alter susceptibility to transformation and changes to mammary stem cell numbers or behaviour. Previous studies have shown that the mammary tissue isolated from both virgin and parous mice has the ability to repopulate a cleared mammary fat pad in transplant experiments. Limited dilution transplant assays have demonstrated that early pregnancy (at 5 weeks of age) reduces stem/progenitor cell numbers in the mouse mammary epithelium by twofold. However, the effects on stem/progenitor cell numbers in the mammary epithelium of a pregnancy in older animals have not yet been tested. Methods Mice were put through a full-term pregnancy at 9 weeks of age, when the mammary epithelium is mature. The total mammary epithelium was purified from parous 7-week post-lactation and age-matched virgin mice and analysed by flow cytometry and limiting dilution cleared fat pad transplants. Results There were no significant differences in the proportions of different mammary epithelial cell populations or numbers of CD24+/Low Sca-1- CD49fHigh cells (stem cell enriched basal mammary epithelial compartment). There was no significant difference in stem/progenitor cell frequency based on limiting dilution transplants between the parous and age-matched virgin epithelium. Conclusions Although differences between parous and virgin mammary epithelium at later time points post lactation or following multiple pregnancies cannot be ruled out, there are no differences in stem/progenitor cell numbers between mammary epithelium isolated from parous animals which were mated at 9 weeks old and virgin animals. However, a recent report has suggested that animals that were mated at 5 weeks old have a twofold reduction in stem/progenitor cell numbers. This is of interest given the association between early, but not late, pregnancy and breast cancer risk reduction in humans. However, a mechanistic connection between stem cell numbers and breast cancer risk remains to be established

Genetic Variation at Chromosome 2q13 and Its Potential Influence on Endometriosis Susceptibility Through Effects on the IL-1 Family

Endometriosis is characterized by the growth of epithelial and stromal cells outside the uterine cavity. It has a complex etiology and affects ∼10% of reproductive age women. It is accompanied by a chronic inflammatory response with substantial evidence to indicate genetic susceptibility. The causal genes and their pathways leading to endometriosis, however, are still unknown. Recently, genomewide association studies on endometriosis identified 14 genomic risk loci in women of European and Japanese ancestry. It is becoming increasingly clear that these risk regions are intergenic and thus contribute to disease susceptibility through regulatory mechanisms, most likely mediated through regulation of genes within a restricted distance from the risk variants. One endometriosis risk locus has been detected at chromosome 2q13 within an inflammatory-rich region of gene transcripts and thus may play a role in the inflammation component of the disease. We carried out detailed analysis of the genomic region 250 kb on either side of sentinel SNP rs10167914 and identified 21 transcripts which contained 6 interleukin (IL)-1 family genes, 3 previously reported coding genes that have a relationship to inflammation, 4 novel coding, or pseudogenes, and 8 noncoding RNA transcripts. Through an extensive literature search, we examined the roles these genes and their resultant proteins play in endometriosis pathogenesis. The results suggest alteration in the expression the IL-1 family transcripts either alone or as a complex milieu could have a significant influence on endometriosis and should be prioritized for future study on the implications of inflammation on endometriotic lesions