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Jun 8, 2010

Scientists Identify Target to Prevent Breast Cancer from Developing Resistance to Endocrine Therapy

  • Combining a PI3K pathway inhibitor with endocrine therapy may help prevent estrogen-dependent breast cancers from developing resistance to treatment, claim scientists at Vanderbilt University Medical Center. The researchers found that when they subjected human breast cancer cell lines to long-term estrogen deprivation as a means of mimicking endocrine therapy, the PI3K signaling pathway was triggered in these cells.

    When they then administered a PI3K inhibitor the cells died. Using reverse-phase protein microarrays, the team also identified a breast tumor protein signature of PI3K pathway activation that predicted poor outcome after adjuvant endocrine therapy in patients.

    Their results are published in the online edition of the Journal of Clinical Investigation in a paper titled “Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor–positive human breast cancer.”

    The authors claim their studies suggest PI3K activation represents “a critical hub in the emergence and maintenance of hormone-independent, ER-positive breast cancer cells.” Moreover, their studies in human cell lines showed that while direct inhibition of PI3K effectively suppressed the hormone-independent growth of both estrogen-independent and -dependent cells, inhibition of nodes upstream (RTKs) and downstream (mTOR) of PI3K only partially blocked cell growth.

    “In summary, our findings suggest that patients with hormone receptor-positive tumors exhibiting a high degree of PI3K signaling and patients who relapse on endocrine therapy, may benefit from therapeutics targeting both the ER and the PI3K pathways,” the authors write. “Additionally, inhibition of PI3K prevented the emergence of hormone-independent cells, which suggests that early intervention with combined endocrine and PI3K-directed therapies could limit escape from anti-estrogens in patients with ER-positive breast cancer.”


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