The ER?4 variant induces transformation of the normal breast mammary epithelial cell line MCF-10A; the ER? variants ER?2 and ER?5 increase aggressiveness of TNBC by regulation of hypoxic signaling.

ABSTRACT: Triple negative breast cancer (TNBC) still remains a challenge to treat in the clinic due to a lack of good targets for treatment. Although TNBC lacks expression of ER?, the expression of ER? and its variants are detected quite frequently in this cancer type and can represent an avenue for treatment. We show that two of the variants of ER?, namely ER?2 and ER?5, control aggressiveness of TNBC by regulating hypoxic signaling through stabilization of HIF-1?. RNA-seq of patient derived xenografts (PDX) from TNBC shows expression of ER?2, ER?4 and ER?5 variants in more than half of the samples. Furthermore, expression of ER?4 in the immortalized, normal mammary epithelial cell line MCF-10A that is resistant to tumorsphere formation caused transformation and development of tumorspheres. By contrast, ER?1, ER?2 or ER?5 were unable to support tumorsphere formation. We have previously shown that all variants except ER?1 stabilize HIF-1? but only ER?4 appears to have the ability to transform normal mammary epithelial cells, pointing towards a unique property of ER?4. We propose that ER? variants may be good diagnostic tools and also serve as novel targets for treatment of breast cancer.

SUBMITTER: Faria M 

PROVIDER: S-EPMC5844739 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature