ERα, HOXC11 and Breast Cancer: The Good, the Bad and the Ugly
In Ireland breast cancer one of the most common causes of cancer related death for women. Upon diagnosis approximately two thirds of patients will present with a hormone receptor positive tumour (ER+). The ER pathway plays a pivotal role in breast cancer development and progression. Consequently endocrine therapies to block ER signalling are one of the most prevailing and effective treatment methods to date. However, a growing body of evidence suggests that within a heterogeneous breast tumour a sub-set of pluri-potent cells are capable of evading therapeutic treatment. Subsequently tumours metastasise and patients develop de novo or acquired resistance to endocrine therapies. Continuous activation of growth factor signalling pathways can provide tumours with altered proliferative and survival stimuli. Deregulated epigenetic machinery has also been implicated in the development of resistance. Translational studies from our group and others, has identified the steroid receptor co-activator SRC-1 to be master transcriptional regulator of breast cancer disease progression. Further studies identified the developmental protein and transcription factor HOXC11 as an interacting partner of SRC-1. Interactions between HOXC11 and SRC-1 in breast cancer cell lines and tissue have previously been reported. Their relationship has been shown to be important in tumour progression and metastasis in tamoxifen treated patients. Aberrant expression of HOXC11 has been associated with endocrine resistance. HOXC11 is known to drive the expression of the secreted protein S100P. Both HOXC11 and S100P have been described as tissue and serum biomarkers which can predict response to endocrine therapy. To date however, a functional role for HOXC11 in breast cancer has not been established.
The hypothesis of this thesis is to investigate a functional role for HOXC11 in an endocrine resistant breast cancer phenotype. It will investigate how this developmental transcription factor evades endocrine therapies in order to promote malignant transformation and it will explore the relationship between HOXC11 and ERa and the significance of this relationship at a clinical level.
Aberrant expression of HOXC11 we found confers a malignant phenotype similar to that of the known LY2 tamoxifen resistant cells. We found MCF7 endocrine sensitive breast cancer cells with overexpressed HOXC11 displayed a loss of differentiation and cellular polarity. HOXC11 alone induces proliferation, cell motility and anchorage independence. We observed a novel relationship between HOXC11 and the estrogen receptor alpha (ERa) and found that ERa could tame the aggressive malignant transformations induced by HOXC11. We observed that HOXC11 overexpression downregulates transcriptional regulation of ERa and propose a mechanism of epigenetic regulation in which HOXC11 may be silencing ERa activity. S100P a secreted protein and known HOXC11 target gene was also found to be a target of ERa and we observed HOXC11 and ERa compete for the regulation of S100P depending on the cellular microenvironment.
HOXC11 can mediate malignant transformation and ERa in part can compete with HOXC11 to tame this aggressive phenotype. Tumour transformation is due in part to the altered therapeutic target. At a clinical level this is of significance as we have opened up new avenues in which resistant tumours could be targeted with alternative drug therapies.