Synergistic Activation of ERα by Estrogen and Prolactin in Breast Cancer Cells Requires Tyrosyl Phosphorylation of PAK1

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Published on Friday, 30 November 2018

Abstract

Serine/threonine kinase PAK1 is activated by estrogen and plays an important role in breast cancer. However, the integration of PAK1 into the estrogen response is not fully understood.

In this study, we investigated the mechanisms underlying the hormone-induced activation of estrogen receptor (ERα, ESR1). We show that estrogen activated PAK1 through both the ERα and GPER1 membrane receptors.

Estrogen-dependent activation of PAK1 required the phosphorylation of tyrosine residues by Etk/Bmx and protein kinase A (PKA) within an assembled signaling complex comprising pTyr-PAK1, Etk/Bmx, the heterotrimer G-protein subunits Gβ1, Gγ2, and/or Gγ5, PAK-associated guanine nucleotide exchange factor (βPIX, ARHGEF7), and PKA.

Moreover, the PKA RIIβ subunit is a direct target of PAK1, and thus in response to estrogen, the activated pTyr-PAK1 complex reciprocally potentiated PKA activity, suggesting a positive feedback mechanism.

We also demonstrate that PKA phosphorylated Ser305-ERα in response to estrogen, but pTyr-PAK1 phosphorylated Ser305-ERα in response to prolactin (PRL), implying that maximal ERα phosphorylation is achieved when cells are exposed to both PRL and estrogen.

Furthermore, S305-ERα activation led to enhanced phosphorylation of Ser118-ERα and promoted cell proliferation and tumor growth.

Together, these data strongly support a critical interplay between PRL and estrogen via PAK1 and suggest that ligand-independent activation of ERα through PRL/PAK1 may impart resistance to anti-estrogen therapies.

 

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See also:

- Official Web Site: The Di Bella Method;

- The Di Bella Method (A Fixed Part - Bromocriptine/Cabergoline);

- The Di Bella Method (A Fixed Part - Calcium, 2 grams per day, orally);

- The Synergism of Somatostatin, Melatonin, Vitamins Prolactin and Estrogen Inhibitors Increased Survival, Objective Response and Performance Status In 297 Cases of Breast Cancer;

- Complete objective response, stable for 5 years, with the Di Bella Method, of multiple-metastatic carcinoma of the breast;

- Evaluation of the safety and efficacy of the first-line treatment with somatostatin combined with melatonin, retinoids, vitamin D3, and low doses of cyclophosphamide in 20 cases of breast cancer: a preliminary report;

- The Di Bella Method (DBM) improved survival, objective response and performance status in a retrospective observational clinical study on 122 cases of breast cancer;

- Complete objective response to biological therapy of plurifocal breast carcinoma;

- Somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide in advanced non-small-cell lung cancer patients with low performance status;

- Somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide in chemotherapy-pretreated patients with advanced lung adenocarcinoma and low performance status;

- Observations on the Report of a case of pulmonary adenocarcinoma with lymph node, hepatic and osseus metastasis;

- The Di Bella Method (DBM) in the treatment of prostate cancer: a preliminary retrospective study of 16 patients and a review of the literature.