Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer

Todd W. Miller, Justin M. Balko, Carlos L. Arteaga

Research output: Contribution to journalReview article

238 Citations (Scopus)

Abstract

Although antiestrogen therapies targeting estrogen receptor (ER) α signaling prevent disease recurrence in the majority of patients with hormone-dependent breast cancer, a significant fraction of patients exhibit de novo or acquired resistance. Currently, the only accepted mechanism linked with endocrine resistance is amplification or overexpression of the ERBB2 (human epidermal growth factor receptor 2 [HER2]) proto-oncogene. Experimental and clinical evidence suggests that hyperactivation of the phosphatidylinositol 3-kinase (PI3K) pathway, the most frequently mutated pathway in breast cancer, promotes antiestrogen resistance. PI3K is a major signaling hub downstream of HER2 and other receptor tyrosine kinases. PI3K activates several molecules involved in cell-cycle progression and survival, and in ER-positive breast cancer cells, it promotes estrogen-dependent and -independent ER transcriptional activity. Preclinical tumor models of antiestrogen-resistant breast cancer often remain sensitive to estrogens and PI3K inhibition, suggesting that simultaneous targeting of the PI3K and ER pathways may be most effective. Herein, we review alterations in the PI3K pathway associated with resistance to endocrine therapy, the state of clinical development of PI3K inhibitors, and strategies for the clinical investigation of such drugs in hormone receptor-positive breast cancer.

Original languageEnglish (US)
Pages (from-to)4452-4461
Number of pages10
JournalJournal of Clinical Oncology
Volume29
Issue number33
DOIs
StatePublished - Nov 20 2011

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Phosphatidylinositol 3-Kinase
Estrogen Receptor Modulators
Breast Neoplasms
Estrogen Receptors
Estrogens
Hormones
Proto-Oncogenes
Receptor Protein-Tyrosine Kinases
Cell Survival
Cell Cycle
Recurrence
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. / Miller, Todd W.; Balko, Justin M.; Arteaga, Carlos L.

In: Journal of Clinical Oncology, Vol. 29, No. 33, 20.11.2011, p. 4452-4461.

Research output: Contribution to journalReview article

Miller, Todd W. ; Balko, Justin M. ; Arteaga, Carlos L. / Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. In: Journal of Clinical Oncology. 2011 ; Vol. 29, No. 33. pp. 4452-4461.
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