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Hormonal control of growth factor receptor expression
M De Bortoli1, P Maggiora, D Capello
1Department of Animal Biology, University of Turin, Italy.
Abstract:
In this report, we have discussed a series of results obtained in our laboratory that, together with data by other authors, demonstrate that the expression of the erbB-2 tyrosine kinase receptor oncogene in breast cancer cells is regulated by multiple factors and hormones, which modulate their growth and differentiation. In particular, we have shown that estrogens specifically inhibit erbB-2 expression by transcriptional repression, which is exerted through a sequence within the erbB-2 gene promoter. Estrogens control mammary cell growth directly, by inducing early gene expression, and indirectly, by increasing autocrine growth factor production or decreasing growth inhibitors. The data presented here suggest that mammary cells respond to estrogen also by modifying the receptor array on their surface, thus setting their own sensitivity to the different autocrine and paracrine factors. As a first consequence, the modulation of erbB-2 expression level by antiestrogen may represent a point to consider when selecting breast cancer patients for hormonal therapy, in those (few) cases where estrogen receptor positivity accompanies erbB-2 amplification. On the other hand, antiestrogen-induced upregulation of erbB-2 may improve tumor targeting of drugs designed to interact or interfere with erbB-2, such as humanized antibodies, immunotoxins, or engineered ligands. These possibilities should be tested in appropriate model systems in the future.
Insights
Estrogens inhibit erbB-2 oncogene expression in breast cancer cells via transcriptional repression. This finding has implications for selecting hormonal therapies and developing targeted treatments for breast cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Endocrinology
Background:
- The erbB-2 tyrosine kinase receptor oncogene plays a role in breast cancer cell growth and differentiation.
- Hormonal factors and other signaling molecules regulate erbB-2 expression.
- Estrogen's role in breast cancer is complex, influencing cell growth and receptor expression.
Purpose of the Study:
- To investigate the regulatory mechanisms of erbB-2 expression in breast cancer cells.
- To elucidate the specific role of estrogens in modulating erbB-2 expression.
- To explore the therapeutic implications of targeting erbB-2 in relation to estrogen signaling.
Main Methods:
- Analysis of erbB-2 gene expression in breast cancer cells.
- Investigation of transcriptional regulation by estrogens using gene promoter sequences.
- Assessment of estrogen's effects on mammary cell growth and receptor expression.
Main Results:
- Estrogens specifically inhibit erbB-2 expression through transcriptional repression via the erbB-2 gene promoter.
- Estrogens modulate mammary cell growth by regulating early gene expression and autocrine/paracrine factors.
- Estrogen signaling alters cell surface receptor arrays, influencing sensitivity to growth factors.
Conclusions:
- Modulating erbB-2 expression with antiestrogens could be relevant for selecting hormonal therapy in specific breast cancer cases (ER-positive with erbB-2 amplification).
- Antiestrogen-induced upregulation of erbB-2 may enhance tumor targeting for erbB-2-directed therapies.
- Further research in model systems is warranted to validate these therapeutic strategies.