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Signal transduction pathways activated and required for mammary carcinogenesis in response to specific oncogenes
1Department of Genetics, Harvard Medical School, Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA.
Abstract:
We have assessed five signal transduction pathways to determine the role each might play in the malignant transformation of mammary epithelium initiated by neu, heregulin/NDF, TGFalpha, v-Ha-ras and c-myc in transgenic mice. The study involves a molecular and pharmacologic assessment of Erk/MAP kinase, Jnk/SAP kinase, PI 3-kinase, protein kinase C, and the Src-related kinases Lck and Fyn. Our results indicate that oncogenes capable of transforming mammary gland epithelium activate and require specific signal transduction pathways. For example, mammary tumors initiated by neu, v-Ha-ras and c-myc have high levels of active Erk/MAP kinase and their anchorage independent growth is strongly inhibited by PD098059, an inhibitor of Mek/ MAP kinase kinase. By contrast, Erk/MAP kinase activity is weak in tumors initiated by TFGalpha and heregulin/NDF and the corresponding cell lines are not growth inhibited by PD098059. Similarly, PI 3-kinase is strongly activated in neu, TGFalpha and heregulin/NDF initiated tumor cell lines, but not in c-myc or v-Ha-ras initiated tumor cell lines. The anchorage independent growth of all these tumor cell lines are, however, inhibited by the specific PI 3-kinase inhibitor LY294001. Further illustrating this oncogene-based specificity, PP1, a specific inhibitor of the Src-like kinases, Lck and Fyn, blocks anchorage-independent cell growth only in the TGFalpha initiated mammary tumor cell line. Taken together with additional observations, we conclude that certain oncogenes reliably require the recruitment/activation of specific signal transduction pathways. Such specific relationships between the initiating oncogene and a required pathway may reflect a direct activating effect or the parallel activation of a pathway that is a necessary oncogenic collaborator for transformation in the mammary gland. The work points to a molecular basis for targeting therapy when an initiating oncogene can be implicated; for example, because of amplification, increased expression, genetic alteration, or heritable characteristics.
Insights
Oncogenes driving mammary tumors activate specific cell signaling pathways. Targeting these pathways, like Erk/MAP kinase or PI 3-kinase, offers a molecular basis for tailored cancer therapies.
Area of Science:
- Oncology
- Molecular Biology
- Signal Transduction
Background:
- Malignant transformation of mammary epithelium is a complex process.
- Oncogenes play a critical role in initiating cancer development.
- Understanding the underlying signaling pathways is crucial for targeted therapies.
Purpose of the Study:
- To investigate the roles of five key signal transduction pathways in mammary epithelial transformation.
- To determine the specific pathways activated by different oncogenes (neu, heregulin/NDF, TGFalpha, v-Ha-ras, c-myc).
- To explore the potential for pathway-specific therapeutic targeting in mammary cancer.
Main Methods:
- Molecular and pharmacologic assessment of Erk/MAP kinase, Jnk/SAP kinase, PI 3-kinase, protein kinase C, and Src-related kinases (Lck, Fyn).
- Utilized transgenic mouse models of mammary gland oncogenesis.
- Employed specific pathway inhibitors (PD098059, LY294001, PP1) to assess functional requirements.
Main Results:
- Oncogenes like neu, v-Ha-ras, and c-myc strongly activate Erk/MAP kinase, crucial for anchorage-independent growth.
- TGFalpha and heregulin/NDF initiated tumors show weaker Erk/MAP kinase activity but significant PI 3-kinase activation.
- All tested tumor cell lines' anchorage-independent growth was inhibited by a PI 3-kinase inhibitor, while Src-like kinase inhibition was specific to TGFalpha-initiated tumors.
Conclusions:
- Specific oncogenes driving mammary transformation rely on distinct signal transduction pathways.
- These oncogene-pathway relationships can be direct or involve collaborative pathways.
- Identifying the initiating oncogene and its associated pathway provides a molecular basis for targeted therapeutic strategies in breast cancer.