How to target estrogen receptor-negative breast cancer?

Abstract

Estrogen receptor (ER)-positive breast cancers generally have a better prognosis and are often responsive to anti-estrogen therapy, which is the first example of a successful therapy targeted on a specific protein, the ER. Unfortunately ER-negative breast cancers are more aggressive and unresponsive to anti-estrogens. Other targeted therapies are thus urgently needed, based on breast cancer oncogene inhibition or suppressor gene activation as far as molecular studies have demonstrated the alteration of expression, or structure of these genes in human breast cancer. Using the MDA-MB.231 human breast cancer cell line as a model of ER-negative breast cancers, we are investigating two of these approaches in our laboratory. Our first approach was to transfect the ER or various ER-deleted variants into an ER-negative cell line in an attempt to recover anti-estrogen responsiveness. The unliganded receptor, and surprisingly estradiol, were both found to inhibit tumor growth and invasiveness in vitro and in vivo. The mechanisms of these inhibitions in ER-negative cancer cells are being studied, in an attempt to target the ER sequence responsible for such inhibition in these cancer cells. Another strategy is trying to inhibit the activity or expression of an oncogene specifically overexpressed in most breast cancers. This approach was recently shown by others to be efficient in breast cancer therapy with HER2-Neu oncogene amplification using Herceptin. Without excluding other molecular putative targets, we have focused our research on cathepsin D as a potential target, since it is often overexpressed in aggressive human breast cancers, including ER-negative tumors, and rarely associated with HER2-Neu amplification. Our first results obtained in vitro on cell lines and in vivo in tumor xenografts in nude mice, illustrate that the mode of action of cathepsin D in breast cancer is useful to guide the development of these therapies. In the past 20 years we have learned that the action of cathepsin D is complex and involves both intracellular and extracellular activities due to its proteolytic activity and to interactions with membrane components without catalytic activity. Each of these mechanisms could be potentially inhibited in an attempt to prevent tumor growth. Breast cancer is a very heterogeneous and multigenic disease and different targeted therapies adapted to each category of breast cancer are therefore required. Validated assays in the primary tumor of molecular markers such as ER, HER2-Neu and cathepsin D should help to predict which targeted therapy should be applied to cure breast cancer patients.

FOXA1: Growth inhibitor and a favorable prognostic factor in human breast cancer

“…On the other hand, in ERa-negative MDA-MB-231 cells with forced ERa expression, FOXA1 activated the ER pathway, leading as well to slowed growth. 23 These findings thus further support a growth inhibitory role for FOXA1 in breast cancer. Cell-type dependent transcriptional activity of FOXA proteins is not unique for breast cancer and has also been demonstrated in hepatoma and neuroblastoma cells.…”

“…23 We found that trans- Low FOXA1 (N, %) 5 (6) 11 (14) 12 ( fection of the ERa into MDA-MB-231 cells resulted in upregulation of FOXA1 protein levels (Fig. 3b).…”

Wilms' Tumor 1 Suppressor Gene Mediates Antiestrogen Resistance via Down-Regulation of Estrogen Receptor-α Expression in Breast Cancer Cells

“…Whereas ER-positive tumors tend to be localized and respond well to hormonal manipulation (26), ER-negative tumors are more aggressive, disseminate widely, and do not respond to hormone therapy (5). A number of mechanisms for the development of ERa negativity have been identified (27)(28)(29)(30)(31)(32). This includes hypermethylation of the ERa promoter in f60% of cases (33) and repression by transcription factors such as pRB2/p130 and LMO4 (34,35).…”

Prognostic significance of tumor-related proteases as a function of the estrogen receptor status

“…40 Future directions of our work will be to include and individualize the value of protease measurement in the case of adjuvant chemotherapy and endocrine therapy, in order to select patients according to their prognostic risk, as proposed in NNBC3 trial. In particular, some studies have suggested that cath-D inhibitors might also potentially be capable of reversing anti-estrogen resistance in ER-positive BC that overexpress cath-D.…”