Intrinsic apoptotic pathway activation increases response to anti-estrogens in luminal breast cancers.

Abstract

Estrogen receptor-α positive (ERα+) breast cancer accounts for approximately 70-80% of the nearly 25,0000 new cases of breast cancer diagnosed in the US each year. Endocrine-targeted therapies (those that block ERα activity) serve as the first line of treatment in most cases. Despite the proven benefit of endocrine therapies, however, ERα+ breast tumors can develop resistance to endocrine therapy, causing disease progression or relapse, particularly in the metastatic setting. Anti-apoptotic Bcl-2 family proteins enhance breast tumor cell survival, often promoting resistance to targeted therapies, including endocrine therapies. Herein, we investigated whether blockade of anti-apoptotic Bcl-2 family proteins could sensitize luminal breast cancers to anti-estrogen treatment. We used long-term estrogen deprivation (LTED) of human ERα+ breast cancer cell lines, an established model of sustained treatment with and acquired resistance to aromatase inhibitors (AIs), in combination with Bcl-2/Bcl-xL inhibition (ABT-263), finding that ABT-263 induced only limited tumor cell killing in LTED-selected cells in culture and in vivo. Interestingly, expression and activity of the Bcl-2-related factor Mcl-1 was increased in LTED cells. Genetic Mcl-1 ablation induced apoptosis in LTED-selected cells, and potently increased their sensitivity to ABT-263. Increased expression and activity of Mcl-1 was similarly seen in clinical breast tumor specimens treated with AI + the selective estrogen receptor downregulator fulvestrant. Delivery of Mcl-1 siRNA loaded into polymeric nanoparticles (MCL1 si-NPs) decreased Mcl-1 expression in LTED-selected and fulvestrant-treated cells, increasing tumor cell death and blocking tumor cell growth. These findings suggest that Mcl-1 upregulation in response to anti-estrogen treatment enhances tumor cell survival, decreasing response to therapeutic treatments. Therefore, strategies blocking Mcl-1 expression or activity used in combination with endocrine therapies would enhance tumor cell death.

• Authors: Michelle M Williams, Linus Lee, Thomas Werfel, Meghan M Morrison Joly, Donna J Hicks, Bushra Rahman, David Elion, Courtney McKernan, Violeta Sanchez, Monica V Estrada, Suleiman Massarweh, Richard Elledge, Craig Duvall, Rebecca S Cook
• Journal: Cell death & disease (Cell Death Dis) Vol. 9 Issue 2 Pg. 21 (01 17 2018) ISSN: 2041-4889 [Electronic] England
• PMID: 29343814 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Aniline Compounds
• Estrogen Antagonists
• MCL1 protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• Receptors, Estrogen
• Sulfonamides
• bcl-X Protein
• Fulvestrant
• navitoclax

Topics

• Aniline Compounds (pharmacology)
• Animals
• Apoptosis (drug effects)
• Breast Neoplasms (metabolism, pathology)
• Cell Line, Tumor
• Down-Regulation (drug effects)
• Estrogen Antagonists (pharmacology)
• Female
• Fulvestrant (pharmacology)
• Gene Targeting
• Humans
• Mice
• Myeloid Cell Leukemia Sequence 1 Protein (metabolism)
• Receptors, Estrogen (metabolism)
• Signal Transduction (drug effects)
• Sulfonamides (pharmacology)
• Up-Regulation (drug effects)
• bcl-X Protein (metabolism)