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Published on: August 13, 2019
Oestrogen receptor-beta signalling protects against transplanted skin tumour growth in the mouse
Jun-Lae Cho1, Munif Allanson, Vivienne E Reeve
1Faculty of Veterinary Science, University of Sydney, McMaster Building B14, Sydney, New South Wales 2006, Australia.
Abstract:
We have reported previously that a deficiency in signalling by the non-classical oestrogen receptor-beta (Er-beta) exacerbates immunosuppression by UV radiation in the mouse. Because photoimmune suppression is a risk factor for skin cancer development, we hypothesize that Er-beta deficiency will promote skin tumour growth. Therefore we have blocked Er signalling pharmacologically in the Skh:hr-1 hairless mouse by topical treatments with the Er antagonist ICI 182,780, and genetically in haired mice by using the specific Er-beta knockout mouse (targeted mutation of the Er-beta), and examined the growth rate of 3 transplantable skin tumour cell lines in their syngeneic host mice. Two UV-induced squamous cell carcinoma (SCC) cell lines transplanted into the Skh:hr-1 recipients were found to have regressor qualities that were delayed by prior immunosuppressive solar-simulated UV (SSUV) irradiation. For the T79 SCC, regression was significantly further delayed by combined pretreatment with SSUV+ICI 182,780, and the diameters of the surviving tumours were slightly larger. For the KL3.0 SCC, both SSUV and combined SSUV+ICI 182,780 pretreatments completely inhibited tumour regression, and resulted in significantly greater tumour diameters than in unirradiated recipient mice. In heterozygous Er-beta deficient mice (Er-beta+/-), the B16/F10 melanoma grew progressively and significantly faster than in the wild type control mice (C57BL/6), and growth rate was accelerated by prior SSUV irradiation. Homozygous Er-beta-/- mice supported the most rapid B16/F10 growth that was further accelerated by prior SSUV irradiation. Therefore Er signalling, specifically by Er-beta, has a natural endogenous protective role against skin tumour growth, probably mediated via immunological pathways.
Insights
Oestrogen receptor-beta (Er-beta) deficiency worsens UV-induced immunosuppression and promotes skin tumor growth. Blocking Er signalling or genetic deficiency accelerates tumor progression, indicating Er-beta
Area of Science:
- Immunology
- Dermatology
- Endocrinology
Background:
- UV radiation causes immunosuppression, a risk factor for skin cancer.
- Non-classical oestrogen receptor-beta (Er-beta) signaling deficiency exacerbates UV-induced immunosuppression.
- The role of Er-beta in skin tumor development requires further investigation.
Purpose of the Study:
- To investigate the role of oestrogen receptor-beta (Er-beta) signaling in skin tumor growth.
- To determine if Er-beta deficiency promotes skin tumor development.
- To examine the impact of blocking Er signaling on UV-induced skin tumors.
Main Methods:
- Pharmacological blockade of Er signaling using ICI 182,780 in hairless mice.
- Genetic deficiency of Er-beta using knockout mice.
- Transplantation of UV-induced squamous cell carcinoma (SCC) and melanoma cell lines.
- Assessment of tumor growth rates and regression in response to UV irradiation and Er antagonist treatment.
Main Results:
- Er-beta deficiency and pharmacological blockade of Er signaling significantly delayed tumor regression and increased tumor size.
- UV-induced SCC regression was further inhibited by combined UV and Er antagonist treatment.
- B16/F10 melanoma growth was accelerated in heterozygous and homozygous Er-beta deficient mice, especially after UV irradiation.
Conclusions:
- Oestrogen receptor-beta (Er-beta) signaling plays a protective role against skin tumor growth.
- Er-beta mediated protection is likely linked to immunological pathways.
- Targeting Er-beta signaling may offer a therapeutic strategy for preventing or treating skin cancer.
