Connections between HP1(Hsalpha) and breast cancer invasion/metastasis

Metastasis is the major cause of death from breast cancer. A woman diagnosed with a primary breast tumor has a 98% five-year survival rate. As the tumor progresses and becomes regionally invasive, the rate declines to 85%. In contrast, a woman diagnosed with metastatic breast cancer has only a 26% five-year survival rate. These statistics highlight the need for better understanding of breast cancer progression. Heterochromatin Protein 1Hsalpha (HP1 Hsalpha) is differentially expressed between invasive and noninvasive breast cancer cell lines. This correlates with in vivo data showing primary breast tumors have high levels of HP1Hsalpha while distant metastases have low levels. HP1Hsalpha is a protein involved in chromatin organization that regulates gene expression. Therefore, we hypothesized that HP1Hsalpha acts as a metastasis suppressor by regulating gene transcription. Previous results showed that over-expression of exogenous HP1Hsalpha in highly invasive breast cancer cells reduced in vitro invasion, without altering growth rate. Data presented here show that reduction of HP1Hsalpha levels by RNAi in poorly invasive breast cancer cells causes a 50% increase in invasion, without altering growth rate. Gene expression profiling upon reduction of HP1Hsalpha showed ∼400 genes differentially expressed compared to control cells. Among the misexpressed genes were those involved in known cancer pathways, such as estrogen response and CXCR4 signaling. In addition, specific DNA motifs that bind transcription factors such as Rb/E2F1 and YY1 were enriched in the promoters of misregulated genes. These results suggest that known cancer pathways are affected by HP1Hsalpha levels, possibly through transcriptional control. Additionally, some candidate genes showed reciprocal response to changes in HP1Hsalpha levels in breast cancer cell lines with different invasive potentials.;For example, a reduction of HP1Hsalpha in a poorly invasive, nonmetastatic cell line led to increased CXCR4 expression, while over-expression of HP1Hsalpha in a highly invasive, metastatic cell decreased CXCR4 expression, suggesting that genes known to primarily affect invasion and metastasis are proportionally responsive to HP1Hsalpha levels. These data support HP1Hsalpha as a putative metastasis suppressor and provide an epigenetic regulatory pathway for breast cancer progression as a target for new therapeutic regimens.