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Prevention of mammary carcinogenesis in MMTV-neu mice by targeting RLIP
Jyotsana Singhal1,2, Prakash Kulkarni1, David Horne2
1Departments of Medical Oncology, City of Hope Comprehensive Cancer Center and National Medical Center, Duarte, California, USA.
Abstract:
The overexpression and amplification of the protooncogene neu (ERBB2) play an important role in the development of aggressive breast cancer (BC) in humans. Ral-interacting protein (RLIP), a modular stress-response protein with pleiotropic functions, is overexpressed in several types of cancer, including BC. Here, we show that blocking RLIP attenuates the deleterious effects caused by the loss of the tumor suppressor p53 and inhibits the growth of human BC both in vitro and in vivo in MMTV-neu mice. In addition, we show that treatment with the diet-derived, RLIP-targeting chemotherapeutic 2'-hydroxyflavanone (2HF), alone or in combination with RLIP-specific antisense RNA or antibodies, significantly reduced the cumulative incidence and/or burden of mammary hyperplasia and carcinoma in MMTV-neu mice. 2HF treatment correlated with reduced tumor cell proliferation and increased apoptosis, and the average number of Ki67-positive (proliferating) cells was significantly lower in the tumors of 2HF-treated mice than in the tumors of control mice. Furthermore, targeting RLIP also resulted in the overexpression of E-cadherin and the infiltration of CD3+ T cells into mammary tumors. Taken together, these results underscore the translational potential of RLIP-targeting agents and provide a strong rationale to validate them in the clinic.
Insights
Blocking Ral-interacting protein (RLIP) inhibits aggressive breast cancer growth. A diet-derived compound, 2-hydroxyflavanone (2HF), targeting RLIP, reduced tumor burden and increased apoptosis in mice.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Protooncogene neu (ERBB2) amplification drives aggressive human breast cancer (BC).
- Ral-interacting protein (RLIP) is overexpressed in various cancers, including BC, and has diverse functions.
- Tumor suppressor p53 loss contributes to cancer progression.
Purpose of the Study:
- To investigate the role of RLIP in breast cancer development and progression.
- To evaluate the efficacy of RLIP-targeting agents, including 2'-hydroxyflavanone (2HF), in preclinical models of breast cancer.
Main Methods:
- In vitro and in vivo studies using human BC cells and MMTV-neu mouse models.
- Treatment with 2HF, RLIP-specific antisense RNA, or antibodies.
- Assessment of tumor growth, proliferation (Ki67), apoptosis, E-cadherin expression, and T cell infiltration (CD3+).
Main Results:
- Blocking RLIP inhibited human BC growth in vitro and in vivo.
- 2HF treatment significantly reduced mammary hyperplasia and carcinoma incidence/burden in MMTV-neu mice.
- 2HF therapy decreased tumor cell proliferation and increased apoptosis, with higher E-cadherin and CD3+ T cell infiltration.
Conclusions:
- Targeting RLIP, particularly with 2HF, shows significant therapeutic potential for aggressive breast cancer.
- RLIP inhibition offers a promising strategy to counteract p53 loss effects and reduce tumor growth.
- These findings support the clinical validation of RLIP-targeting agents for breast cancer treatment.
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