Blocking the PAH2 domain of Sin3A inhibits tumorigenesis and confers retinoid sensitivity in triple negative breast cancer.
Triple negative breast cancer (TNBC) frequently relapses locally, regionally or as systemic metastases. Development of targeted therapy that offers significant survival benefit in TNBC is an unmet clinical need. We have previously reported that blocking interactions between PAH2 domain of chromatin regulator Sin3A and the Sin3 interaction domain (SID) containing proteins by SID decoys result in EMT reversal, and re-expression of genes associated with differentiation. Here we report a novel and therapeutically relevant combinatorial use of SID decoys. SID decoys activate RARα/β pathways that are enhanced in combination with RARα-selective agonist AM80 to induce morphogenesis and inhibit tumorsphere formation. These findings correlate with inhibition of mammary hyperplasia and a significant increase in tumor-free survival in MMTV-Myc oncomice treated with a small molecule mimetic of SID (C16). Further, in two well-established mouse TNBC models we show that treatment with C16-AM80 combination has marked anti-tumor effects, prevents lung metastases and seeding of tumor cells to bone marrow. This correlated to a remarkable 100% increase in disease-free survival with a possibility of "cure" in mice bearing a TNBC-like tumor. Targeting Sin3A by C16 alone or in combination with AM80 may thus be a promising adjuvant therapy for treating or preventing metastatic TNBC.
The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Nidhi
N
Bansal
The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Almudena
A
Bosch
The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Boris
B
Leibovitch
Division of Hemato-Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA.
Lutecia
L
Pereira
Division of Hemato-Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA.
Elena
E
Cubedo
Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, Baltimore, MD, USA.
Jianshi
J
Yu
Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, Baltimore, MD, USA.
Keely
K
Pierzchalski
Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, Baltimore, MD, USA.
Jace W
JW
Jones
The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Melissa
M
Fishel
Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, Baltimore, MD, USA.
Maureen
M
Kane
Division of Hemato-Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA.
Arthur
A
Zelent
The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Samuel
S
Waxman
The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Eduardo
E
Farias
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D063646:Carcinogenesis / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018168:Receptors, Retinoic Acid / Q000819:agonists; D012097:Repressor Proteins / Q000037:antagonists & inhibitors*; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology; D064726:Triple Negative Breast Neoplasms / Q000473:pathology*
D000970:Antineoplastic Agents; D001565:Benzoates; C000617853:GW 506033X; D007211:Indoles; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D013764:Tetrahydronaphthalenes; D013844:Thiazoles; C000611841:retinoic acid receptor beta2, mouse; C061133:tamibarotene; D056264:Sin3 Histone Deacetylase and Corepressor Complex
SID decoys; Sin3A; metastases; retinoids; triple negative breast cancer