Change in the subcellular localization of MI-ER1α is associated with breast cancer progression

The typical progression of normal breast tissue to an invasive breast carcinoma involves a series of steps that include an increase in the number of breast cells (hyperplasia), an increase in the number of abnormal cells (atypical hyperplasia) and then the development of an in situ carcinoma. An in situ carcinoma means that cancer is present but it still confined to the site where the abnormal growth originally developed, the ducts (ductal carcinoma in situ) or the lobules (lobular carcinoma in situ). The cancer cells that comprise this in situ cancer can then undergo further changes allowing them to become invasive and spread into the surrounding tissues. In situ carcinomas are often referred to as pre-cancerous since individuals who are diagnosed with having such are at an increased risk for developing breast carcinoma. -- The incidence of breast cancer is increasing across Canada, which is suspected to be a result of an increase in mammographic screening. This often translates into detection of the carcinoma in its earliest stages when the treatment response is optimal and the prognosis is more favorable. However, for many, the cancer is advanced and therefore may have limited treatment options. Also, there are individuals who have the option of treatment upon diagnosis, and still unfortunately have a high likelihood of recurrence. Yet again, there are individuals for whom the cancer is found in the early stages, but have a short disease-free period following treatment. In such cases, it may be that the tumor(s) is resistant to the treatment they received. For all of these reasons there is a need for improved screening methods, improved prognostic indicators and improved therapeutic regimes. -- Estrogen receptor-alpha (ERα) is one of the steroid hormone receptors that plays a role in normal growth and development of the breast; it has also long been implicated in breast tumorigenesis. Many of the current breast cancer treatments target the action of the estrogen receptor (ER) indirectly; by blocking either the ability of the ER ligand, estrogen, from binding to the receptor or the synthesis of estrogen. Hence, ERα expression could potentially guide physicians in predicting prognosis and devising a treatment plan. -- In an effort to improve upon current standard treatments or devise new, more efficacious therapies, the molecular pathway of ERα needs to be resolved. Human mesoderm induction early response 1 (hMI-ER1) is a key regulator of this pathway through its interaction with ERα. During investigations into the role of fibroblast growth factors (FGFs) in the development and differentiation of Xenopus laevis embryo, MI-ER1 was found to be an initial target of the FGF signal transduction pathway. -- The hmi-er1 gene was cloned and characterized (Paterno et. al., 1998) and shown to have two major protein isoforms, hMI-ER1α and hMI-ER1β. Both isoforms contain a number of motifs characteristic of transcriptional regulators and have been shown to act as repressors of transcription (Paterno, et. al., 1997; Ding, et. al., 2003; Ding, et. al., 2004). The alpha and beta isoforms differ in their C-terminus. hMI-ER1α contains a classic nuclear hormone receptor (NR) co-regulator motif, an LXXLL domain, which is not found within the beta isoform. -- MI-ER1α has been shown to interact with ERα in breast cancer cells, in the presence and absence of estrogen. It was also found to reduce ER-mediated breast cell growth in ER-positive breast cancer cells (McCarthy, et. al., 2008). Theoretically, this data supports a role for MI-ER1α in breast cancer cell proliferation. -- My hypothesis is that MI-ER1α might be differentially expressed in normal breast tissue and breast carcinoma. Immunohistochemical analysis of MI-ERα expression pattern and subcellular localization in both normal breast and breast carcinoma was carried out using 156 whole tissue sections and 771 cases from tissue microarrays. While there was no consistent difference in the level of expression between normal cells and tumor cells, there was a striking difference in the subcellular localization. In normal and hyperplastic breast 72% of the cases had nuclear MI-ER1α, whereas in breast diseases only 51% ductal carcinoma in situ (DCIS), 25% invasive lobular carcinoma (ILC) and only 4% invasive ductal carcinoma (IDC) has nuclear MI-ERα1 staining (McCarthy, P. et. al., 2008). This represents a shift in the subcellular localization of MI-ER1α, from nuclear to cytoplasmic, during breast cancer progression. Such a shift in MI-ER1α localization might then be associated with the progression of breast cancer; hence, MI-ER1α might prove useful for prognostic determination. Hence, it is possible that the lack of nuclear MI-ER1α expression in DCIS lesions will serve as a means of identifying women who are at a higher risk for developing invasive breast carcinoma.