Functional cooperation between GPER and AHR toward breast cancer progression
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Cirillo, Francesca
Cerra, Maria Carmela
Maggiolini, Marcello
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Dottorato in Scienze della Vita. Ciclo XXXI; The cytochrome P450 1B1 (CYP1B1) is a heme-thiolate monooxygenase involved in both
estrogen and environmental contaminants metabolism. For instance, CYP1B1 catalyzes
the hydroxylation of 17-β estradiol (E2) leading to the production of 4-hydroxyestradiol
that may act as a potent carcinogenic agent. In addition, CYP1B1 is overexpressed in
different tumors including breast cancer. In this scenario, it is worth mentioning that
CYP1B1 expression is triggered by estrogens through the estrogen receptor (ER)α in
breast cancer cells. In the present study, we evaluated whether the G protein estrogen
receptor namely GPER may provide an alternate route toward the expression and
function of CYP1B1 in ER-negative breast cancer cells, in cancer-associated fibroblasts
(CAFs) obtained from breast cancer patients, in CAFs derived from a cutaneous metastasis
of an invasive mammary ductal carcinoma and in breast tumor xenografts. Our results
show that GPER along with the EGFR/ERK/c-Fos transduction pathway can lead to CYP1B1
regulation through the involvement of a half-ERE sequence located within the CYP1B1
promoter region. As a biological counterpart, we found that both GPER and CYP1B1
mediate growth effects in vitro and in vivo. Altogether, these data suggest that estrogens
in ER-negative cell contexts may engage the alternate GPER signaling toward CYP1B1
regulation. CYP1B1 is a well-known target gene of the aryl hydrocarbon receptor (AHR)
that may be activated by the carcinogenic pollutant 3-methylcholanthrene (3MC). Hence,
we aimed to provide novel insights into the molecular mechanisms by which 3MC and E2
may activate a cross talk between AHR and GPER transduction pathways leading to the
stimulation of breast cancer cells and CAFs. In particular, our results demonstrate that
3MC and E2 trigger the EGFR/ERK/c-Fos signalling through both AHR and GPER toward
the up-regulation of CYP1B1 and cyclin D1 as well as the stimulation of growth responses.
Altogether, the present findings suggest that a functional interaction between AHR and
GPER may occur toward breast cancer progression; Università della CalabriaSoggetto
Endocrinology; Estrogen; Breast Cancer; Receptors, Aryl Hydrocarbon
Relazione
MED/04;