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ATM Is Required for the Prolactin-Induced HSP90-Mediated Increase in Cellular Viability and Clonogenic Growth After

Ödül Karayazi Atici1,2, Anna Urbanska1,2, Sesha Gopal Gopinathan1,2

  • 1Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada.

Endocrinology
|November 30, 2017
PubMed

Insights

Prolactin (PRL) enhances breast cancer cell survival against DNA damage via the JAK2-STAT5-HSP90 pathway. ATM kinase is crucial, and inhibiting HSP90 or ATM synergizes with chemotherapy.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • Prolactin (PRL) is a survival factor for breast cancer cells.
  • The precise PRL signaling pathway and its mechanism remain largely unknown.
  • Heat shock protein 90 (HSP90) alpha was previously identified as a target gene in the PRL-Janus kinase 2 (JAK2)-signal transducer and activator of transcription 5 (STAT5) pathway.

Purpose of the Study:

  • To investigate the role of HSP90 in PRL-mediated cell viability in response to DNA damage.
  • To elucidate the involvement of the ataxia-telangiectasia mutated (ATM) kinase in this process.
  • To explore potential therapeutic strategies by targeting this pathway.

Main Methods:

  • Utilized breast cancer cell lines treated with DNA-damaging agents (doxorubicin, etoposide).
  • Employed PRL receptor antagonist, HSP90 inhibitors (17-allylamino-17-demethoxygeldanamycin, BIIB021), JAK2 inhibitor (G6), and ATM inhibitor (KU55933).
  • Assessed cell viability, protein levels (JAK2, ATM, p-ATM), and used short interfering RNA (siRNA) against ATM in various culture models.

Main Results:

  • PRL significantly increased breast cancer cell viability following DNA damage, an effect blocked by a PRL receptor antagonist.
  • HSP90 inhibitors reduced PRL-mediated viability and decreased levels of JAK2, ATM, and phosphorylated ATM.
  • Inhibitors of JAK2 and ATM, as well as ATM siRNA, abolished PRL-induced cell survival, confirming pathway involvement and crosstalk.
  • Drug synergism was observed between ATM/HSP90 inhibitors and doxorubicin.

Conclusions:

  • ATM plays a critical role in the PRL-JAK2-STAT5-HSP90 pathway.
  • This pathway mediates cellular resistance to DNA-damaging agents in breast cancer.
  • Targeting HSP90 or ATM may enhance the efficacy of chemotherapy against breast cancer.

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