Breast Tumor Kinase (Brk/PTK6) Is Induced by HIF, Glucocorticoid Receptor, and PELP1-Mediated Stress Signaling in Triple-Negative Breast Cancer

Cancer Research
Tarah M Regan AndersonCarol A Lange

Abstract

Cancer cells use stress response pathways to sustain their pathogenic behavior. In breast cancer, stress response-associated phenotypes are mediated by the breast tumor kinase, Brk (PTK6), via the hypoxia-inducible factors HIF-1α and HIF-2α. Given that glucocorticoid receptor (GR) is highly expressed in triple-negative breast cancer (TNBC), we investigated cross-talk between stress hormone-driven GR signaling and HIF-regulated physiologic stress. Primary TNBC tumor explants or cell lines treated with the GR ligand dexamethasone exhibited robust induction of Brk mRNA and protein that was HIF1/2-dependent. HIF and GR coassembled on the BRK promoter in response to either hypoxia or dexamethasone, indicating that Brk is a direct GR/HIF target. Notably, HIF-2α, not HIF-1α, expression was induced by GR signaling, and the important steroid receptor coactivator PELP1 was also found to be induced in a HIF-dependent manner. Mechanistic investigations showed how PELP1 interacted with GR to activate Brk expression and demonstrated that physiologic cell stress, including hypoxia, promoted phosphorylation of GR serine 134, initiating a feed-forward signaling loop that contributed significantly to Brk upregulation. Collectively, our findings ...Continue Reading

References

Jun 6, 1995·Proceedings of the National Academy of Sciences of the United States of America·G L WangG L Semenza
May 3, 2003·Oncology Research·Michael S Serfas, Angela L Tyner
Apr 26, 2005·International Journal of Cancer. Journal International Du Cancer·Jean-Philippe DalesColette Charpin
Jul 5, 2006·Clinical Endocrinology·Peter J RaubenheimerJonathan R Seckl
Sep 7, 2007·Breast Cancer Research and Treatment·Yutaka YamamotoHirotaka Iwase
Aug 1, 2008·Breast Cancer Research and Treatment·Larissa BelovaSuzanne D Conzen
Aug 7, 2008·American Journal of Physiology. Endocrinology and Metabolism·Midori KayaharaDavid W Ray
Aug 23, 2008·Proceedings of the National Academy of Sciences of the United States of America·Bin XiangSenthil K Muthuswamy
Feb 17, 2009·Current Oncology Reports·C Lance Cowey, W Kimryn Rathmell
May 28, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Rakesh KumarSuresh K Rayala
Oct 31, 2009·Applied Immunohistochemistry & Molecular Morphology : AIMM·Frederic BuxantJean-Christophe Noël
Jul 6, 2010·Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation·Daniel WolffHildegard Greinix
Jul 30, 2010·PloS One·Hanna Y IrieJoan S Brugge
Sep 14, 2010·Current Opinion in Pharmacology·Julie H OstranderCarol A Lange
Sep 21, 2011·Molecular and Cellular Biology·Amy Jo Galliher-BeckleyJohn Anthony Cidlowski
Aug 28, 2012·Trends in Molecular Medicine·Gregg L Semenza
Sep 25, 2012·Nature·UNKNOWN Cancer Genome Atlas Network
May 30, 2013·Nature Communications·Preethi RavindranathanGanesh V Raj
Aug 10, 2013·Cancer Research·Tarah M Regan AndersonCarol A Lange
Sep 7, 2014·Cancer Research·Cinzia MartinengoRoberto Chiarle
Mar 20, 2015·Breast Cancer Research and Treatment·Samaya R KrishnanRatna K Vadlamudi
May 28, 2015·Acta Dermato-venereologica·Adèle C Green, Catherine M Olsen
Jul 15, 2015·Molecular Endocrinology·Preethi RavindranathanGanesh V Raj

❮ Previous
Next ❯

Citations

Feb 3, 2016·Journal of Molecular Endocrinology·Katherine A LeehyJulie H Ostrander
Oct 21, 2016·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Margarita Arango-Lievano, Freddy Jeanneteau
Nov 1, 2016·Hormones & Cancer·Shawna B Matthews, Carol A Sartorius
Apr 21, 2020·Neuro-oncology Advances·Gangadhara R SareddyRatna K Vadlamudi
Jul 20, 2019·Cancer Biomarkers : Section a of Disease Markers·Chuanyu MaMinglei Luo
Apr 11, 2018·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Diana C WestSuzanne D Conzen
Jul 12, 2018·Molecular Cancer Research : MCR·Tarah M Regan AndersonCarol A Lange
May 1, 2021·International Journal of Molecular Sciences·Lara Malik NoureddineCoralie Poulard
Apr 21, 2018·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·Christopher I McHughAnthony F Shields
Jun 17, 2021·Essays in Biochemistry·Carlos Perez KerkvlietCarol A Lange

❮ Previous
Next ❯

Related Concepts

Related Feeds

Breast Invasive Carcinoma

Invasive breast cancers indicate a spread into breast tissues and lymph nodes. Here are the latest discoveries pertaining to breast invasive carcinomas.

Breast Cancer Triple-N

Breast cancer cells have receptors for estrogen, progesterone, HER2 receptors (also called ERBB2). Triple-negative breast cancers do not have any of these receptors. Here are the latest discoveries pertaining to triple-negative breast cancers.

Breast Invasive Carcinoma (Keystone)

Invasive breast cancers indicate a spread into breast tissues and lymph nodes. Here are the latest discoveries pertaining to breast invasive carcinomas.