Summary1 Unlike non-clonal plants, clonal plants can develop a division of labour in which connected ramets specialize to acquire different, locally abundant resources. This occurs as a plastic response to a patchy environment where two resources tend not to occur together and different ramets experience high availabilities of different resources. We hypothesized that if division of labour is an important advantage of clonal growth in such environments in nature, then clones from habitats where resource availabilities are negatively associated should show a greater capacity for division of labour than clones from habitats where resource availabilities are more uniform. 2 To test this, we collected clones of Fragaria chiloensis from sand dune and grassland sites in each of three regions of the central coast of California, grew pairs of connected or severed ramets under low light and high N or under high light and low N, and measured leaf area, chlorophyll content and final dry mass. Given that previous work has indicated that high availabilities of light and N show a stronger tendency not to occur together in the dune than in the grassland sites, we expected that clones from dunes would show greater capacity for division of labour than clones from grasslands. 3 Clones from dunes showed a greater capacity than clones from grasslands to specialize for acquisition of abundant N via high proportional mass of roots. Clones from the two types of habitats showed similar capacity to specialize for acquisition of abundant light via high leaf area and chlorophyll content of leaves. Specialization via leaf area and chlorophyll content took place mainly within the first half of the 60-day experiment. 4 These results provide evidence that division of labour in a clonal plant has been selected for in natural habitats where high levels of different resources tend to be spatially separated. Results also show that division of labour can occur, not just via allocation of mass, but also via physiological traits, and that both morphological and physiological specialization can take place within a few weeks. 5 Clonal plants dominate many habitats and include many highly invasive species. Division of labour is one of the most striking potential advantages of clonal growth, and is a remarkable instance of phenotypic plasticity in plants. This study further suggests that division of labour in clonal plants is an instance of adaptive plasticity and could therefore play a part in their widespread ecological success.

Chemical manipulation of estrogen receptor alpha ligand binding domain structural mobility tunes receptor lifetime and influences breast cancer therapeutic activities. Selective estrogen receptor modulators (SERMs) extend ERα cellular lifetime/accumulation. They are antagonists in the breast but agonists in the uterine epithelium and/or in bone. Selective estrogen receptor degraders/downregulators (SERDs) reduce ERα cellular lifetime/accumulation and are pure antagonists. Activating somatic ESR1 mutations Y537S and D538G enable resistance to first-line endocrine therapies. SERDs have shown significant activities in ESR1 mutant setting while few SERMs have been studied. To understand whether chemical manipulation of ERα cellular lifetime and accumulation influences antagonistic activity, we studied a series of methylpyrollidine lasofoxifene derivatives that maintained the drug's antagonistic activities while uniquely tuning ERα cellular accumulation. These molecules were examined alongside a panel of antiestrogens in live cell assays of ERα cellular accumulation, lifetime, SUMOylation, and transcriptional antagonism. High-resolution x-ray crystal structures of WT and Y537S ERα ligand binding domain in complex with the methylated lasofoxifene derivatives or representative SERMs and SERDs show that molecules that favor a highly buried helix 12 antagonist conformation achieve the greatest transcriptional suppression activities in breast cancer cells harboring WT/Y537S ESR1. Together these results show that chemical reduction of ERα cellular lifetime is not necessarily the most crucial parameter for transcriptional antagonism in ESR1 mutated breast cancer cells. Importantly, our studies show how small chemical differences within a scaffold series can provide compounds with similar antagonistic activities, but with greatly different effects of the cellular lifetime of the ERα, which is crucial for achieving desired SERM or SERD profiles.

Estrogen receptor alpha (ERα) is a ligand-dependent master transcriptional regulator and key driver of breast cancer pathology. Small molecule hormones and competitive antagonists favor unique ERα conformational ensembles that elicit ligand-specific transcriptional programs in breast cancer and other hormone-responsive tissues. By affecting disparate ligand binding domain structural features, unconventional ligand scaffolds can redirect ERα genomic binding patterns to engage novel therapeutic transcriptional programs. To improve our understanding of these ERα structure-transcriptional relationships, we develop a series of chemically unconventional antagonists based on the antiestrogens elacestrant and lasofoxifene. High-resolution x-ray co-crystal structures show that these molecules affect both classical and unique structural motifs within the ERα ligand binding pocket. They show moderately reduced antagonistic potencies on ERα genomic activities but are effective anti-proliferative agents in luminal breast cancer cells. Interestingly, they favor a 4-hydroxytamoxifen-like accumulation of ERα in breast cancer cells but lack uterotrophic activities in an endometrial cell line. Importantly, RNA sequencing shows that the lead molecules engage transcriptional pathways similar to the selective estrogen receptor degrader fulvestrant. This advance shows that fulvestrant-like genomic activities can be achieved without affecting ERα accumulation in breast cancer cells.

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Estrogen receptor alpha (ERα) is a ligand-dependent master transcriptional regulator and key driver of breast cancer pathology. Small molecule hormones and competitive antagonists favor unique ERα conformational ensembles that elicit ligand-specific transcriptional programs in breast cancer and other hormone-responsive tissues. By affecting disparate ligand binding domain structural features, unconventional ligand scaffolds can redirect ERα genomic binding patterns to engage novel therapeutic transcriptional programs. To improve our understanding of these ERα structure-transcriptional relationships, we have developed a series of chemically unconventional antagonists based on the antiestrogens RAD1901 and lasofoxifene. High-resolution x-ray co-crystal structures show that these molecules affect both classical and unique structural motifs within the ERα ligand binding pocket. They show moderately reduced antagonistic potencies on ERα genomic activities but are effective anti-proliferative agents in luminal breast cancer cells. Interestingly, they show SERM-like ERα accumulation in breast cancer cells but lack uterotrophic activities in an endometrial cell line. RNA sequencing shows that the lead molecules mediate transcriptional pathways similar to fulvestrant and other SERDs in these cells. This advance shows that fulvestrant-like genomic activities can be achieved without affecting ERα accumulation in breast cancer cells.