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

Michelle M Williams,Monica V Estrada,Bushra Rahman,Violeta Sanchez,Thomas Werfel,Meghan M Morrison Joly,Suleiman Massarweh,David Elion,Rebecca S Cook,Craig Duvall,Donna J Hicks,Linus Lee,Richard Elledge,Courtney Mckernan

doi:10.1038/s41419-017-0072-x

Michelle M Williams, Monica V Estrada + Show 12 more

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https://doi.org/10.1038/s41419-017-0072-x

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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.

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Introduction The American CancerSociety estimated that approximately 25,0000 women were diagnosed with breast cancer in 2016 in the United States alone[1]
Since previous studies show that antiapoptotic Bcl-2 family members Bcl-2 and Bcl-xL promote cell survival in tamoxifen-treated breast cancers[13], we measured expression of Bcl-2 and Bcl-xL in parental and long-term estrogen deprivation (LTED)-selected breast cancer cells, finding similar levels of Bcl-2 and Bcl-xL in LTED-selected HCC1428 and T47D cells as compared to their parental counterpoints cultured in estrogen-replete media (Fig. 1c)
The trend towards BIK upregulation in HCC1428-LTED cells over parental HCC1428 cells did not reach statistical significance, together these findings suggest that estrogen receptor-α (ERα)+ breast cancer cells respond to sustained estrogen deprivation through BIK and Mcl-1 upregulation.[33, 34]

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Introduction

Introduction The American CancerSociety estimated that approximately 25,0000 women were diagnosed with breast cancer in 2016 in the United States alone[1]. ERα+ breast cancer cell lines, HCC1428, MCF7, and T47D, were cultured under estrogen deprivation for 3–6 months as described in previous studies[26].

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