Could it be possible that aberrant cholesterol biosynthesis supports malignant transformation carried out by oncogenes, and tamoxifen resistance?

1. Synchronicity between oncogenes and cholesterol biosynthesis in breast cancer? Part II: Is cholesterol biosynthesis linked to endocrine therapy response in breast cancer? Previously I have reported in my blog that elevated levels of mRNA of squaleneepoxidase (SQLE), an enzyme on cholesterol biosynthesis pathway, is frequently found in estrogen positive (ER+) breast cancer that responds poorly to endocrine therapy. My additional research on the same ER+ breast cancer gene-expression profiles that produced the above SQLE-result revealed that DHCR7, an enzyme that catalyzes the final step in cholesterol biosynthesis, the conversion of 7-dehydrocholesterol to cholesterol, has it’s mRNA frequently upregulated in ER+ breast cancer that expresses high levels of SQLE mRNA. As demonstrated in Fig. 1, aco-expression of elevated levels of SQLE and DHCR7 is frequently found in breast cancer that responds poorly to endocrine therapy (tamoxifen). Curiously, SQLE and DHCR7 reside on chromosome 8q24 and 11q13, respectively. The former is the locus for proto-oncogene c-myc, and the latter is found adjacent to 11q14, the home for proto-oncogene cyclin D1 (ccnd1). Dysregulation, including upregulation of the expression of these two proto-oncogenes by genetic aberrations has been implicated in pathogenesis of breast cancer in a number of previous studies. Taken together, could it be possible that aberrant cholesterol biosynthesis supports malignant transformation carried out by oncogenes as well as resistance to tamoxifen-therapy? -MehisPold, M.D. mehisp@hotmail.com October 2, 2010 Figure 1. Poor responders to endocrine therapy as defined in my previous blog entry (ER+ samples within the boxed area) harbor upregulation of both SQLE and DHCR7. Specifically, poor responders to endocrine therapy = expressors of elevated levels of SQLE mRNA. The mRNA levels of DHCR7 in the samples defined as ‘poor responders to endocrine therapy’ express significantly higher levels of DHCR7 as compared to the rest of the cohort (p = 1E-04, Z-test). The above graph resulted from gene-expression data found in GEO dataset GSE12093. An unrelated ER+ breast cancer dataset, GSE17705, produced the same data as above (data not shown). Both of the above GEO datasets previously linked the elevated levels of SQLE mRNA to poor endocrine treatment response. Copyright © Eomix, Inc.