ERβ-TP53 Interaction Targeting for Triple-Negative Breast Cancer
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Solution Overview
Problem
Current targeted therapies for triple negative breast cancer (TNBC) are ineffective due to the lack of expression of estrogen receptor-alpha (ERα), progesterone receptor (PR), or human epidermal growth factor 2 (HER-2) receptor, and cytotoxic chemotherapy has long-term ineffectiveness, necessitating new therapeutic targets and strategies.
Innovation Solution
Administering an agent that increases estrogen receptor beta (ERβ) protein expression in cancer cells expressing mutant tumor protein 53 (TP53) to induce cancer cell death, or inhibiting ERβ and TP53 binding interaction in cells with wildtype TP53 to induce cell death.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If targeted therapies are designed for breast cancer receptors (ERα, PR, HER-2), then treatment effectiveness is improved for cancers expressing these receptors, but treatment effectiveness deteriorates for triple negative breast cancer (TNBC) which lacks these receptors
Solution Approach 1:
The patent changes the therapeutic parameter from targeting absent receptors (ERα, PR, HER-2) to targeting present receptors (ERβ). By identifying that ERβ is expressed in TNBC cells while traditional targets are absent, the invention shifts the therapeutic approach to match the actual molecular profile of TNBC, thereby resolving the contradiction between treatment effectiveness and applicability to TNBC
Solution Approach 2:
The patent introduces ERβ as an intermediary target that connects the therapeutic approach to TNBC treatment. Since ERβ is expressed in TNBC cells and can be modulated by existing drugs like tamoxifen, it serves as a viable intermediary that enables targeted therapy in cancers previously considered untreatable by receptor-targeted approaches
2Productivity
If cytotoxic chemotherapy is used to treat TNBC, then initial tumor response may be achieved, but long-term effectiveness deteriorates due to resistance and lack of sustained benefit
Solution Approach 1:
The patent extracts the mechanism of action from non-specific cytotoxic chemotherapy to a specific molecular pathway involving ERβ and mutant p53 interaction. By isolating and targeting the specific molecular mechanism present in TNBC cells (ERβ-mutant p53 binding), the therapy achieves both initial response and sustained effectiveness, overcoming the limitations of broad-spectrum chemotherapy
Solution Approach 2:
The patent utilizes the feedback mechanism where ERβ expression and mutant p53 status create a specific therapeutic vulnerability. The therapy exploits the feedback loop between ERβ and mutant p53, where increased ERβ expression leads to enhanced binding with mutant p53 and subsequent cell death, providing a self-amplifying therapeutic effect that maintains long-term effectiveness
3Reliability
If ERβ expression is increased in cancer cells with mutant TP53, then cancer cell death is induced through ERβ-mutant TP53 interaction, but this strategy may not be effective in cells with wildtype TP53
Solution Approach 1:
The patent applies local quality by tailoring the therapeutic approach to the specific TP53 status of the cancer cells. For cells with mutant TP53, the strategy is to increase ERβ expression to exploit the pathological interaction. For cells with wildtype TP53, the approach would differ, as the normal p53-ERβ interaction does not lead to cell death. This localized therapeutic strategy based on molecular profiling resolves the contradiction between effective cell death induction and broad applicability
Data Source
Figure 1A~1D
Figure 1E~1G
Figure 1H~1K
AI summary
To induce cancer cell death, cancer cells are selected that express estrogen-receptor β (ERβ) and mutant tumor protein 53 (TP53). An agent that increases ERβ protein expression is administered to the cells to induce cell death. To treat a subject having a cancer that is characterized by cancer cells expressing ERβ and mutant TP53, an agent that increases ERβ protein expression is administered to induce cell death in the cancer cells. To increase estrogen receptor β (ERβ) expression levels in a subject having low ERβ expression levels, tamoxifen is administered to increase ERβ protein levels in the subject. To treat a subject having cancer cells expressing estrogen-receptor β (ERβ) and wildtype tumor protein 53 (TP53), an agent that inhibits ERβ and TP53 binding interaction is administered to induce cell death in the cancer cells of the subject.