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KAT6A, and its paralog KAT6B, are histone lysine acetyltransferases (HAT) that acetylate histone H3K23 and exert an oncogenic role in several tumor types including breast cancer where KAT6A is frequently amplified/overexpressed. However, pharmacologic targeting of KAT6A to achieve therapeutic benefit has been a challenge. Here we describe identification of a highly potent, selective, and orally bioavailable KAT6A/KAT6B inhibitor CTx-648 (PF-9363), derived from a benzisoxazole series, which demonstrates anti-tumor activity in correlation with H3K23Ac inhibition in KAT6A over-expressing breast cancer. Transcriptional and epigenetic profiling studies show reduced RNA Pol II binding and downregulation of genes involved in estrogen signaling, cell cycle, Myc and stem cell pathways associated with CTx-648 anti-tumor activity in ER-positive (ER+) breast cancer. CTx-648 treatment leads to potent tumor growth inhibition in ER+ breast cancer in vivo models, including models refractory to endocrine therapy, highlighting the potential for targeting KAT6A in ER+ breast cancer., Competing Interests: Declaration of interests S.S., T.A.P., C.Y.C., S.U., J.P., J.C., A.R., N.N., S.G., E.J., O.B., S.K., H.W., Z.W., Y.Z., K.T., L.C., A.M., J.L., P.P.K., S.S., P.F.R., E.C.G., S.Y., R.J., K.A.M., P.B., and H.L. are/were employees of Pfizer and some of the authors are shareholders in Pfizer Inc. L.C. and A.M. are co-inventors on patent WO2022013369. P.S., H.R.L., B.J.M., R.F., C.H., M.C., Y.B., and S.W. are inventors on patent WO2019243491 and have received payments from Monash University derived from distribution of licensing income received from Pfizer. P.P.K., S.S., P.F.R., Y.B., and P.S. are inventors on patent WO2020254946. P.S. is an inventor on patent WO2022013369. T.T., H.R.L and A.K.V. are inventors on patent WO2016198507 A1. The Thomas and Voss laboratories received research funding from the Cooperative Research Centre (CRC) for Cancer Therapeutics (CTx), Australia. T.T. and A.K.V. have received payments from a distribution of the licensing income from Pfizer for serving on an advisory board meeting for Pfizer. M.A.D. has been a member of advisory boards for CTX CRC, GSK, Storm Therapeutics, Celgene and Cambridge Epigenetix. S.-J.D. has been a member of advisory boards for Adela. M.A.D. and S.-J.D. receive research funding from CTx CRC and from the Pfizer Emerging Science Fund. Ian Street is a member of the Scientific Advisory Board of Oncology One Pty Ltd and has received payments from distribution of licensing income from Pfizer. J.N. is currently an adjunct professor at the University of New South Wales, Kensington, NSW, Australia. M.J.D and D.D.B. are currently working at South Australian immunoGENomics Cancer Institute (SAiGENCI), Faculty of Health and Medical Sciences, The University of Adelaide. J.C. is a current employee of oNKo-innate Pty Ltd. J.L. is currently an employee and shareholder of Belharra Therapeutics., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Breast cancer remains a leading cause of cancer-related mortality in women, reflecting profound disease heterogeneity, metastasis, and therapeutic resistance. Over the last decade, genomic and transcriptomic data have been integrated on an unprecedented scale and revealed distinct cancer subtypes, critical molecular drivers, clonal evolutionary trajectories, and prognostic signatures. Furthermore, multi-dimensional integration of high-resolution single-cell and spatial technologies has highlighted the importance of the entire breast cancer ecosystem and the presence of distinct cellular "neighborhoods." Clinically, a plethora of new targeted therapies has emerged, now being rapidly incorporated into routine care. Resistance to therapy, however, remains a crucial challenge for the field., Competing Interests: Declaration of interests G.J.L. has had consulting/advisory roles with AbbVie and Pfizer and received institutional support for investigator-initiated clinical trials from Amgen, AbbVie, Genentech (Roche), and Pfizer. The Walter and Eliza Hall Institute of Medical Research receives milestone and royalty payments related to venetoclax. Employees are entitled to receive benefits related to these payments; G.J.L. and J.E.V. report receiving benefits., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Breast tumors are inherently heterogeneous, but the evolving cellular organization through neoplastic progression is poorly understood. Here we report a rapid, large-scale single-cell resolution 3D imaging protocol based on a one-step clearing agent that allows visualization of normal tissue architecture and entire tumors at cellular resolution. Imaging of multicolor lineage-tracing models of breast cancer targeted to either basal or luminal progenitor cells revealed profound clonal restriction during progression. Expression profiling of clones arising in Pten/Trp53-deficient tumors identified distinct molecular signatures. Strikingly, most clones harbored cells that had undergone an epithelial-to-mesenchymal transition, indicating widespread, inherent plasticity. Hence, an integrative pipeline that combines lineage tracing, 3D imaging, and clonal RNA sequencing technologies offers a comprehensive path for studying mechanisms underlying heterogeneity in whole tumors., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Long-lived quiescent mammary stem cells (MaSCs) are presumed to coordinate the dramatic expansion of ductal epithelium that occurs through the different phases of postnatal development, but little is known about the molecular regulators that underpin their activation. We show that ablation of the transcription factor Foxp1 in the mammary gland profoundly impairs ductal morphogenesis, resulting in a rudimentary tree throughout life. Foxp1-deficient glands were highly enriched for quiescent Tspan8 hi MaSCs, which failed to become activated even in competitive transplantation assays, thus highlighting a cell-intrinsic defect. Foxp1 deletion also resulted in aberrant expression of basal genes in luminal cells, inferring a role in cell-fate decisions. Notably, Foxp1 was uncovered as a direct repressor of Tspan8 in basal cells, and deletion of Tspan8 rescued the defects in ductal morphogenesis elicited by Foxp1 loss. Thus, a single transcriptional regulator Foxp1 can control the exit of MaSCs from dormancy to orchestrate differentiation and development., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The prosurvival protein BCL-2 is frequently overexpressed in estrogen receptor (ER)-positive breast cancer. We have generated ER-positive primary breast tumor xenografts that recapitulate the primary tumors and demonstrate that the BH3 mimetic ABT-737 markedly improves tumor response to the antiestrogen tamoxifen. Despite abundant BCL-XL expression, similar efficacy was observed with the BCL-2 selective inhibitor ABT-199, revealing that BCL-2 is a crucial target. Unexpectedly, BH3 mimetics were found to counteract the side effect of tamoxifen-induced endometrial hyperplasia. Moreover, BH3 mimetics synergized with phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors in eliciting apoptosis. Importantly, these two classes of inhibitor further enhanced tumor response in combination therapy with tamoxifen. Collectively, our findings provide a rationale for the clinical evaluation of BH3 mimetics in therapy for breast cancer., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The mammary epithelium is a dynamic, highly hormone-responsive tissue. To explore chromatin modifications underlying its lineage specification and hormone responsiveness, we determined genome-wide histone methylation profiles of mammary epithelial subpopulations in different states. The marked differences in H3K27 trimethylation between subpopulations in the adult gland suggest that epithelial cell-fate decisions are orchestrated by polycomb-complex-mediated repression. Remarkably, the mammary epigenome underwent highly specific changes in different hormonal contexts, with a profound change being observed in the global H3K27me3 map of luminal cells during pregnancy. We therefore examined the role of the key H3K27 methyltransferase Ezh2 in mammary physiology. Its expression and phosphorylation coincided with H3K27me3 modifications and peaked during pregnancy, driven in part by progesterone. Targeted deletion of Ezh2 impaired alveologenesis during pregnancy, preventing lactation, and drastically reduced stem/progenitor cell numbers. Taken together, these findings reveal that Ezh2 couples hormonal stimuli to epigenetic changes that underpin progenitor activity, lineage specificity, and alveolar expansion in the mammary gland., (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)

The cancer stem cell (CSC) model has been established as a cellular mechanism that contributes to phenotypic and functional heterogeneity in diverse cancer types. Recent observations, however, have highlighted many complexities and challenges: the CSC phenotype can vary substantially between patients, tumors may harbor multiple phenotypically or genetically distinct CSCs, metastatic CSCs can evolve from primary CSCs, and tumor cells may undergo reversible phenotypic changes. Although the CSC concept will have clinical relevance in specific cases, accumulating evidence suggests that it will be imperative to target all CSC subsets within the tumor to prevent relapse., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The recent identification of mouse mammary stem cells (MaSCs) and progenitor subpopulations has enhanced the prospect of investigating the genetic control of their lineage specification and differentiation. Here we have explored the role of the Notch pathway within the mammary epithelial hierarchy. We show that knockdown of the canonical Notch effector Cbf-1 in the MaSC-enriched population results in increased stem cell activity in vivo as well as the formation of aberrant end buds, implying a role for endogenous Notch signaling in restricting MaSC expansion. Conversely, Notch was found to be preferentially activated in the ductal luminal epithelium in vivo and promoted commitment of MaSCs exclusively along the luminal lineage. Notably, constitutive Notch signaling specifically targeted luminal progenitor cells for expansion, leading to hyperplasia and tumorigenesis. These findings reveal key roles for Notch signaling in MaSCs and luminal cell commitment and further suggest that inappropriate Notch activation promotes the self-renewal and transformation of luminal progenitor cells.

E2F transcription factors are major regulators of cell proliferation. The diversity of the E2F family suggests that individual members perform distinct functions in cell cycle control. E2F4 and E2F5 constitute a defined subset of the family. Until now, there has been little understanding of their individual biochemical and biological functions. Here, we report that simultaneous inactivation of E2F4 and E2F5 in mice results in neonatal lethality, suggesting that they perform overlapping functions during mouse development. Embryonic fibroblasts isolated from these mice proliferated normally and reentered from Go with normal kinetics compared to wild-type cells. However, they failed to arrest in G1 in response to p16INK4a. Thus, E2F4 and E2F5 are dispensable for cell cycle progression but necessary for pocket protein-mediated G1 arrest of cycling cells.

B-lymphoid and myeloid development are markedly perturbed in a unique transgenic mouse strain, max 41. Pro-B, pre-B, and B lymphocytes were severely reduced but granulocytes were greatly elevated. This phenotype could be adoptively transferred with bone marrow cells. It was not alleviated by bcl-2 or myc transgenes that promote lymphocyte survival or proliferation. Bitransgenic myc/max 41 mice developed pre-B cell lymphoma. An accompanying massive granulocytosis unexpectedly proved to be clonally derived from the pre-B lymphoma cells. These observations suggest that B lymphopoiesis in max 41 mice has been diverted to granulocyte production. Since neither cell type expressed the transgene, this novel lymphomyeloid deviation probably reflects insertional alteration of a hematopoietic regulatory gene.