IBYME   02675
INSTITUTO DE BIOLOGIA Y MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
PR Rapid and Genomic Effects Participate in the Response of Breast Cancer Cells to Tamoxifen
Autor/es:
GALIGNIANA NM, DÍAZ FLAQUÉ MC, VENTURUTTI L, MERCOGLIANO MF, DE MARTINO M, IZZO F, PROIETTI CJ, ELIZALDE PV
Reunión:
Congreso; 96th Endocrine Society Meeting; 2014
Resumen:
The progesterone receptor (PR) is known to participate in breast cancer cell
proliferation and to cross-talk with the oestrogen receptor alpha (ERα), yet its roles
in resistance to anti-oestrogen therapies are not fully understood. In the present
work, we studied the effects of the synthetic progestin medroxyprogesterone
acetate (MPA) alone or in combination with tamoxifen (Tam), a commonly used
selective ER modulator, in Tam-sensitive and -resistant breast cancer cell lines.
We used Tam at a concentration (1 μM) in which it acts as an antagonist of ERα-
mediated effects and therefore mimics its expected role in patients. We found that
Tam inhibited MPA-induced activation of the c-Src/ERK1/2 signaling pathway in
BT474-HR cells, which are sensitive to the antiproliferative effects of Tam. As a
result, two synergic downstream effector mechanisms were disrupted. On the one
hand, Western blot and chromatin immunoprecipitation assays revealed that MPAinduced
c-Src/ERK1/2 phosphorylation and recruitment of the transcription factor
AP-1 to the cyclin D1 promoter, along with ERα and PR itself, were inhibited by cotreating
BT474-HR cells with MPA+Tam. This prevented MPA from inducing cyclin
D1 transcription and cell proliferation. Interestingly, Tam failed to block MPAactivation
of c-Src/ERK1/2 and assembly of the said complex in the Tam-resistant
cell line BT474 (1). On the other hand, we found that PR-dependent activation of c-
Src/ERK1/2 leads to the activation of c-Myc and subsequent down-regulation of
miR-16, a microRNA we have previously shown acts as a tumor suppressor in
progestin-induced breast cancer growth (2). This decrease in miR-16 levels
resulted in increased expression of its target, the anti-apoptotic protein Bcl-2. Cotreatment
of BT474-HR cells with MPA+Tam disrupted MPA activation of c-
Src/ERK1/2, restoring miR-16 levels to control levels and keeping Bcl-2 expression
repressed. Such inhibitory effects of Tam were not evidenced in BT474 cells.
Together, these results suggest that Tam effects on PR-dependent c-Src/ERK1/2
signaling can inhibit cell proliferation by regulating the formation of transcription
factor complexes whilst inducing apoptosis through control of microRNA levels only
in Tam-sensitive cells. Our results provide insight into complex synergic
mechanisms underlying Tam resistance involving the PR, a receptor not classically
studied in the context of ER-targeted therapies shown here to be a possible
therapeutic target to prevent its unrestrained functions in Tam-resistant cells.