HOX genes: Major actors in resistance to selective endocrine response modifiers

Long term treatment with therapies aimed at blocking the estrogen- (ER) or androgen receptor (AR) action often leads to the development of resistance to selective modulators of the estrogen receptor (SERMs) in ERα-positive breast cancer, or of the androgen receptor (SARMs) in AR-positive prostate cancer. Many underlying molecular events that confer resistance are known, but a unifying theme is yet to be revealed. Receptor tyrosine kinases (RTKs) such EGFR, ERBB2 and IGF1R are major mediators that can directly alter cellular response to the SERM, tamoxifen, but the mechanisms underlying increased expression of RTKs are not clear. A number of HOX genes and microRNAs and non-coding RNAs residing in the HOX cluster, have been identified as important independent predictors of endocrine resistant breast cancer. Recently, convincing evidence has accumulated that several members belonging to the four different HOX clusters contribute to endocrine therapy resistant breast cancer, but the mechanisms remain obscure. In this article, we have reviewed recent progress in understanding of the functioning of HOX genes and regulation of their expression by hormones. We also discuss, in particular, the contributions of several members of the HOX gene family to endocrine resistant breast cancer.