Estrogen Therapy Induces Receptor-Dependent DNA Damage Enhanced by PARP Inhibition in ER+ Breast Cancer.

PURPOSE: Clinical evidence indicates that treatment with estrogens elicits anticancer effects in ∼30% of patients with advanced endocrine-resistant estrogen receptor α (ER)-positive breast cancer. Despite the proven efficacy of estrogen therapy, its mechanism of action is unclear and this treatment remains underused. Mechanistic understanding may offer strategies to enhance therapeutic efficacy. EXPERIMENTAL DESIGN: We performed genome-wide CRISPR/Cas9 screening and transcriptomic profiling in long-term estrogen-deprived ER+ breast cancer cells to identify pathways required for therapeutic response to the estrogen 17ß-estradiol (E2). We validated findings in cell lines, patient-derived xenografts (PDX), and patient samples, and developed a novel combination treatment through testing in cell lines and PDX models. RESULTS: Cells treated with E2 exhibited replication-dependent markers of DNA damage and the DNA damage response prior to apoptosis. Such DNA damage was partially driven by the formation of DNA:RNA hybrids (R-loops). Pharmacologic suppression of the DNA damage response via PARP inhibition with olaparib enhanced E2-induced DNA damage. PARP inhibition synergized with E2 to suppress growth and prevent tumor recurrence in BRCA1/2-mutant and BRCA1/2-wild-type cell line and PDX models. CONCLUSIONS: E2-induced ER activity drives DNA damage and growth inhibition in endocrine-resistant breast cancer cells. Inhibition of the DNA damage response using drugs such as PARP inhibitors can enhance therapeutic response to E2. These findings warrant clinical exploration of the combination of E2 with DNA damage response inhibitors in advanced ER+ breast cancer, and suggest that PARP inhibitors may synergize with therapeutics that exacerbate transcriptional stress.

Estrogen therapy induces receptor-dependent DNA damage enhanced by PARP inhibition in ER+ breast cancer.

Purpose: Clinical evidence indicates that treatment with estrogens elicits anti-cancer effects in ∼30% of patients with advanced endocrine-resistant estrogen receptor alpha (ER)-positive breast cancer. Despite the proven efficacy of estrogen therapy, its mechanism of action is unclear and this treatment remains under-utilized. Mechanistic understanding may offer strategies to enhance therapeutic efficacy. Experimental Design: We performed genome-wide CRISPR/Cas9 screening and transcriptomic profiling in long-term estrogen-deprived (LTED) ER+ breast cancer cells to identify pathways required for therapeutic response to the estrogen 17ß-estradiol (E2). We validated findings in cell lines, patient-derived xenografts (PDXs), and patient samples, and developed a novel combination treatment through testing in cell lines and PDX models. Results: Cells treated with E2 exhibited replication-dependent markers of DNA damage and the DNA damage response prior to apoptosis. Such DNA damage was partially driven by the formation of DNA:RNA hybrids (R-loops). Pharmacological suppression of the DNA damage response via poly(ADP-ribose) polymerase (PARP) inhibition with olaparib enhanced E2-induced DNA damage. PARP inhibition synergized with E2 to suppress growth and prevent tumor recurrence in BRCA1/2 -mutant and BRCA1 /2-wild-type cell line and PDX models. Conclusions: E2-induced ER activity drives DNA damage and growth inhibition in endocrine-resistant breast cancer cells. Inhibition of the DNA damage response using drugs such as PARP inhibitors can enhance therapeutic response to E2. These findings warrant clinical exploration of the combination of E2 with DNA damage response inhibitors in advanced ER+ breast cancer, and suggest that PARP inhibitors may synergize with therapeutics that exacerbate transcriptional stress.

Draft Genome Sequence of Xanthobacter aminoxidans ATCC BAA-299T.

Xanthobacter aminoxidans is a Gram-negative pleomorphic and diazotrophic Knallgas bacillus that undergoes asymmetric budding of V-shaped branched cells during cell division. Like other Xanthobacter spp., cells are yellow from production of zeaxanthine dirhamnoside. We sequenced strain 14aT (= ATCC BAA-299T) and report a genome size of 5,829,486 bp with a G+C content of 67.9%.

AMPK Activation by Metformin Promotes Survival of Dormant ER+ Breast Cancer Cells.

PURPOSE: Despite adjuvant endocrine therapy for patients with estrogen receptor alpha (ER)-positive breast cancer, dormant residual disease can persist for years and eventually cause tumor recurrence. We sought to deduce mechanisms underlying the persistence of dormant cancer cells to identify therapeutic strategies. EXPERIMENTAL DESIGN: Mimicking the aromatase inhibitor-induced depletion of estrogen levels used to treat patients, we developed preclinical models of dormancy in ER+ breast cancer induced by estrogen withdrawal in mice. We analyzed tumor xenografts and cultured cancer cells for molecular and cellular responses to estrogen withdrawal and drug treatments. Publicly available clinical breast tumor gene expression datasets were analyzed for responses to neoadjuvant endocrine therapy. RESULTS: Dormant breast cancer cells exhibited upregulated 5' adenosine monophosphate-activated protein kinase (AMPK) levels and activity, and upregulated fatty acid oxidation. While the antidiabetes AMPK-activating drug metformin slowed the estrogen-driven growth of cells and tumors, metformin promoted the persistence of estrogen-deprived cells and tumors through increased mitochondrial respiration driven by fatty acid oxidation. Pharmacologic or genetic inhibition of AMPK or fatty acid oxidation promoted clearance of dormant residual disease, while dietary fat increased tumor cell survival. CONCLUSIONS: AMPK has context-dependent effects in cancer, cautioning against the widespread use of an AMPK activator across disease settings. The development of therapeutics targeting fat metabolism is warranted in ER+ breast cancer.

Draft Genome Sequence of Xanthobacter tagetidis ATCC 700314T.

Xanthobacter tagetidis is a thiophene-degrading bacterium associated with root balls of the plant genus Tagetes, which includes marigolds. It is a Gram-negative facultatively autotrophic bacterium with pleomorphic morphology exhibiting bent and branching rods. From strain TagT2CT (= ATCC 700314T), we report a genome assembly of 4,945,221 bp and a 69.5% G+C content.

Genome Sequence of Kurthia Type Species Kurthia zopfii Strain ATCC 33403T.

The genome of the type strain of the Kurthia genus, Kurthia zopfii ATCC 33403, was sequenced. Nonpathogenic K. zopfii has been isolated from intestinal contents, fecal material, meats, meat products, milk, water, and air, including air at high altitudes. The predicted genome size is 2,878,279 bp, with 37.05% G+C content.

Genome Sequences for Three Strains of Kocuria rosea, Including the Type Strain.

Genomes from three strains of Kocuria rosea were sequenced. K. rosea ATCC 186, the type strain, was 3,958,612 bp in length with a total G+C content of 72.70%. When assembled, K. rosea ATCC 516 was 3,862,128 bp with a 72.82% G+C content. K. rosea ATCC 49321 was 4,018,783 bp in size with a 72.49% G+C content.

Draft Genome Sequence of the Psychrotolerant Bacterium Kurthia sibirica ATCC 49154T.

The aerobic, Gram-positive, psychrotolerant bacterium Kurthia sibirica was first isolated from the stomach and intestinal contents of the Magadan mammoth recovered from the permafrost in eastern Siberia in 1977. K. sibirica was sequenced, and the predicted genome size is 3,496,665 bp, with 36.42% G+C content.