Research Interests: bisphenol A and In situ
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1) To investigate expression of the E3 ligase, RNF126, in human invasive breast cancer (BC) and its links with BC outcomes. 2) To test the hypothesis that RNF126 determines the efficacy of inhibitors targeting the cell cycle checkpoint... more
1) To investigate expression of the E3 ligase, RNF126, in human invasive breast cancer (BC) and its links with BC outcomes. 2) To test the hypothesis that RNF126 determines the efficacy of inhibitors targeting the cell cycle checkpoint kinase, CHK1. A retrospective analysis by immunohistochemistry (IHC) compared RNF126 staining in 110 invasive BC and 78 paired adjacent normal tissues with clinicopathologic data. Whether RNF126 controls CHK1 expression was determined by chromatin immunoprecipitation and a CHK1 promoter driven luciferase reporter. Staining for these two proteins by IHC using tissue microarrays was also conducted. Cell killing/replication stress induced by CHK1 inhibition was evaluated in cells, with or without RNF126 knockdown, by MTT/colony formation, replication stress biomarker immunostaining and DNA fiber assays. RNF126 protein expression was elevated in BC tissue samples. RNF126 was associated with a poor clinical outcome after multivariate analysis and was an in...
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Research Interests: Molecular Biology, Biology, Medicine, Gene expression, In Situ Hybridization, and 15 moreBiological Sciences, Placenta, Mice, Female, Animals, Polymerase Chain Reaction, Promoter, Horses, Plasmids, Pituitary Gland, Base Sequence, DNA probes, Biology Reproduction, Molecular Sequence Data, and Medical and Health Sciences
Technological and computational advances in genomics and interactomics have made it possible to identify how disease mutations perturb protein-protein interaction (PPI) networks within human cells. Here, we show that disease-associated... more
Technological and computational advances in genomics and interactomics have made it possible to identify how disease mutations perturb protein-protein interaction (PPI) networks within human cells. Here, we show that disease-associated germline variants are significantly enriched in sequences encoding PPI interfaces compared to variants identified in healthy subjects from the 1000 Genomes and ExAC projects. Somatic missense mutations are also significantly enriched in PPI interfaces compared to non-interfaces in 10,861 tumor exomes. We computationally identified 470 putative oncoPPIs in a pan-cancer analysis and demonstrate that the oncoPPIs are highly correlated with patient survival and drug resistance/sensitivity. We experimentally validate the network effects of 13 oncoPPIs using a systematic binary interaction assay, and also demonstrate the functional consequences of two of them on tumor cell growth. In summary, this human interactome network framework provides a powerful tool for prioritizing alleles with PPI perturbing mutations to inform pathobiological mechanism and genotype-based therapeutic discovery.
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Kaplan-Meier plot demonstrating that ESR1 expression predicts recurrence-free survival similarly to FST in a cohort of over 2800 patients with breast cancer (all subtypes). Patients are stratified in high- and low-expressing groups for... more
Kaplan-Meier plot demonstrating that ESR1 expression predicts recurrence-free survival similarly to FST in a cohort of over 2800 patients with breast cancer (all subtypes). Patients are stratified in high- and low-expressing groups for ESR1 using optimal cutoffs in the KM Plotter data analysis tool [58]. (PPTX 84 kb)
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Follistatin inhibits activin A-induced invasion without impacting proliferation. a MCF10A and 4 T1 cells were treated with vehicle, recombinant human activin A (100 ng/ml), or activin A plus recombinant human FST (400 ng/ml), and cell... more
Follistatin inhibits activin A-induced invasion without impacting proliferation. a MCF10A and 4 T1 cells were treated with vehicle, recombinant human activin A (100 ng/ml), or activin A plus recombinant human FST (400 ng/ml), and cell number was assessed by MTS assay after 72 h. b MCF10A cells that overexpress rat c-Neu (10ANeu) were treated with vehicle, activin A (100 ng/ml), or activin A plus FST (400 ng/ml) for 48 h and plated for invasion assays in modified Boyden chambers + Matrigel overnight with serum as a chemoattractant in addition to follistatin and/or activin A (*p
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FST expression is reduced in breast cancer cell lines compared with nontransformed mammary epithelial cells. a Western blot analysis of breast cancer cell lines demonstrating loss of FST expression compared with nontransformed (NT)... more
FST expression is reduced in breast cancer cell lines compared with nontransformed mammary epithelial cells. a Western blot analysis of breast cancer cell lines demonstrating loss of FST expression compared with nontransformed (NT) mammary epithelial cells. b FST expression in MCF10A versus MCF10A-Neu stable cell lines that overexpress rat c-Neu/ErbB2 [27]. FST was assessed by quantitative RT-PCR relative to TATA-binding protein (TBP) mRNA (**pâ
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Supplementary methods. (DOCX 21 kb)
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FST overexpression in mouse mammary epithelia. a Follistatin-like 3 (Fstl3) is downregulated in HER 2/Neu-induced mouse mammary tumors compared with normal mammary glands. Fstl3 expression in mammary glands and HER 2/Neu tumors was... more
FST overexpression in mouse mammary epithelia. a Follistatin-like 3 (Fstl3) is downregulated in HER 2/Neu-induced mouse mammary tumors compared with normal mammary glands. Fstl3 expression in mammary glands and HER 2/Neu tumors was determined using data from a published microarray study of these tumors (*p
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FST expression is associated with overall survival and metastasis in multiple cohorts of patients with breast cancer. Tumors are stratified into the highest 10% and lowest (remaining 90%) FST-expressing groups for each dataset as follows:... more
FST expression is associated with overall survival and metastasis in multiple cohorts of patients with breast cancer. Tumors are stratified into the highest 10% and lowest (remaining 90%) FST-expressing groups for each dataset as follows: Curtis et al. [54] reported FST low (n = 1774), FST high (n = 197); Hatzis et al. [53] reported FST low (n = 457), FST high (n = 51); and Kao et al. [55] reported FST low (n = 294), FST high (n = 33). FST expression does not predict recurrence to bone in the Bos et al. cohort [24]: FST low (n = 149), FST high (n = 17). (PPTX 109 kb)
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The phenotypes of each breast cancer subtype are defined by their transcriptomes. However, the transcription factors that regulate differential patterns of gene expression that contribute to specific disease outcomes are not well... more
The phenotypes of each breast cancer subtype are defined by their transcriptomes. However, the transcription factors that regulate differential patterns of gene expression that contribute to specific disease outcomes are not well understood. Here, using gene silencing and overexpression approaches, RNA-Seq, and splicing analysis, we report that the transcription factor B-cell leukemia/lymphoma 11A (BCL11A) is highly expressed in triple-negative breast cancer (TNBC) and drives metastatic disease. Moreover, BCL11A promotes cancer cell invasion by suppressing the expression of muscleblind-like splicing regulator 1 (MBNL1), a splicing regulator that suppresses metastasis. This ultimately increases the levels of an alternatively spliced isoform of integrin-α6 (ITGA6), which is associated with worse patient outcomes. These results suggest that BCL11A sustains TNBC cell invasion and metastatic growth by repressing MBNL1-directed splicing of ITGA6. Our findings also indicate that BCL11A lies at the interface of transcription and splicing and promotes aggressive TNBC phenotypes.
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Glioblastoma (GBM) remains refractory to treatment. In addition to its cellular and molecular heterogeneity, epidemiological studies indicate the presence of additional complexity associated with biological sex. GBM is more prevalent and... more
Glioblastoma (GBM) remains refractory to treatment. In addition to its cellular and molecular heterogeneity, epidemiological studies indicate the presence of additional complexity associated with biological sex. GBM is more prevalent and aggressive in male compared to female patients, suggesting the existence of sex-specific growth, invasion, and therapeutic resistance mechanisms. While sex-specific molecular mechanisms have been reported at a tumor cell-intrinsic level, sex-specific differences in the tumor microenvironment have not been investigated. Using transgenic mouse models, we demonstrate that deficiency of junctional adhesion molecule-A (JAM-A) in female mice enhances microglia activation, GBM cell proliferation, and tumor growth. Mechanistically, JAM-A suppresses anti-inflammatory/pro-tumorigenic gene activation via interferon-activated gene 202b (Ifi202b) and found in inflammatory zone (Fizz1) in female microglia. Our findings suggest that cell adhesion mechanisms functi...
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Research Interests: Endocrinology, Biology, Medicine, Biological Sciences, Molecular, and 15 moreGrowth Hormone, Cell Differentiation, Internal Medicine, Mice, Female, Animals, Male, Cell Death, Adrenocorticotropic Hormone, Base Sequence, Luteinizing Hormone, Follicle stimulating hormone, Diphtheria Toxin, hypogonadism, and Medical and Health Sciences
The 18-bp direct repeat occurring between positions -146 and -111 in the 5'-flanking region of the human alpha-subunit gene serves two functions: it mediates the transcriptional effect of cAMP and it acts in conjunction... more
The 18-bp direct repeat occurring between positions -146 and -111 in the 5'-flanking region of the human alpha-subunit gene serves two functions: it mediates the transcriptional effect of cAMP and it acts in conjunction with an adjacent cis-acting element (URE) to confer properties of placental-specific expression to the alpha-subunit promoter. Functional activity of the URE and CRE requires binding of a trans-acting factor; each element binds a different factor. Analysis of saturation isotherms provides good evidence that cooperativity is involved in binding of CREB to the 18-bp direct repeat. This cooperativity could account for the synergistic effect of two CRE on both basal and cAMP-stimulated transcription. It remains to be determined whether heterotropic cooperativity is involved in binding of trans-acting factors to the URE and CRE. A major difference between the 5'-flanking region of the human alpha-subunit gene and comparable regions from bovine, rat, and mouse alpha-subunit genes is that the latter contain a single CRE homolog which appears incapable of binding the trans-acting factor that binds to the human alpha CRE. Lack of a functional CRE provides at least one explanation for inactivity of the bovine alpha-subunit promoter in choriocarcinoma cells and probably in bovine placenta as well. Yet, the same bovine promoter-regulatory region that lacks a functional CRE is capable of conferring pituitary-specific expression to the CAT gene in transgenic mice (data not shown). This suggests that the CRE is not required for pituitary-specific expression of the bovine alpha-subunit gene. Instead, another cis-acting element(s) must confer this property to the alpha-subunit promoter. While it is tempting to suggest that bovine, rat, and mouse alpha-subunit genes are not regulated by cAMP because of their inactive CRE homolog, it is also quite possible that other CRE are located further upstream. Accordingly, it will be of interest to obtain additional 5'-flanking sequence and determine whether functional homologs of the human alpha CRE are present in the bovine, rat, and mouse alpha-subunit genes, or whether another class of cis-acting elements provide cAMP-responsiveness.
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Breast cancer is a collection of distinct tumor subtypes that are driven by unique gene expression profiles. These transcriptomes are controlled by various epigenetic marks that dictate which genes are expressed and suppressed. During... more
Breast cancer is a collection of distinct tumor subtypes that are driven by unique gene expression profiles. These transcriptomes are controlled by various epigenetic marks that dictate which genes are expressed and suppressed. During carcinogenesis, extensive restructuring of the epigenome occurs, including aberrant acetylation, alteration of methylation patterns, and accumulation of epigenetic readers at oncogenes. As epigenetic alterations are reversible, epigenome-modulating drugs could provide a mechanism to silence numerous oncogenes simultaneously. Here, we review the impact of inhibitors of the Bromodomain and Extraterminal (BET) family of epigenetic readers in breast cancer. These agents, including the prototypical BET inhibitor JQ1, have been shown to suppress a variety of oncogenic pathways while inducing minimal, if any, toxicity in models of several subtypes of breast cancer. BET inhibitors also synergize with multiple approved anti-cancer drugs, providing a greater res...
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The PI3K/AKT/mTORC1 pathway is a major therapeutic target for many cancers, particularly breast cancer. Everolimus is an mTORC1 inhibitor used in metastatic estrogen receptor-positive (ER+) and epidermal growth factor receptor 2-negative... more
The PI3K/AKT/mTORC1 pathway is a major therapeutic target for many cancers, particularly breast cancer. Everolimus is an mTORC1 inhibitor used in metastatic estrogen receptor-positive (ER+) and epidermal growth factor receptor 2-negative (HER2-) breast cancer. However, mTORC1 inhibitors have limited efficacy in other breast cancer subtypes. We sought to discover collateral sensitivities to mTORC1 inhibition that could be exploited to improve therapeutic response. Using a mouse model of breast cancer that is intrinsically resistant to mTORC1 inhibition, we found that rapamycin alters the expression of numerous extracellular matrix genes, suggesting a potential role for integrins/FAK in controlling mTORC1-inhibitor efficacy. FAK activation was also inversely correlated with rapamycin response in breast cancer cell lines. Supporting its potential utility in patients, FAK activation was observed in >50% of human breast cancers. While blocking FAK in mouse models of breast cancer that...
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The pioneering function of FOXA1 establishes estrogen-responsive transcriptomes in luminal breast cancer. Dysregulated FOXA1 chromatin occupancy through focal amplification, mutation, or cofactor recruitment modulates estrogen receptor... more
The pioneering function of FOXA1 establishes estrogen-responsive transcriptomes in luminal breast cancer. Dysregulated FOXA1 chromatin occupancy through focal amplification, mutation, or cofactor recruitment modulates estrogen receptor (ER) transcriptional programs and drives endocrine-resistant disease. However, ER is not the sole nuclear receptor (NR) expressed in breast cancers, nor is it the only NR for which FOXA1 serves as a licensing factor. Receptors for androgens, glucocorticoids, and progesterone are also found in the majority of breast cancers, and their functions are also impacted by FOXA1. These NRs interface with ER transcriptional programs and, depending on their activation level, can reprogram FOXA1-ER cistromes. Thus, NR interplay contributes to endocrine therapy response and resistance and may provide a vulnerability for future therapeutic benefit in patients. Herein, we review what is known regarding FOXA1 regulation of NR function in breast cancer in the context ...
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Cancers are, first and foremost, a disease of unrestrained proliferation. Although other cancer hallmarks aid and abet advanced disease, the most effective therapies are those that disrupt proliferation [1]. Selective drivers of tumor... more
Cancers are, first and foremost, a disease of unrestrained proliferation. Although other cancer hallmarks aid and abet advanced disease, the most effective therapies are those that disrupt proliferation [1]. Selective drivers of tumor growth have been identified for several cancer types, and targeted therapies to these factors have significantly extended patient outcomes [2–5]. For the majority of cancers, non-selective chemotherapies remain the most effective for achieving regression of both primary and metastatic lesions. Despite their efficacy at targeting proliferating cells, chemotherapeutic drugs typically have a narrow therapeutic window due to off-target toxicity, and many patients develop resistance, underscoring the need for more effective and safer options for patients. With recent discoveries, it is becoming increasingly apparent that the drivers of proliferation itself may function in a tissue-specific manner [6]. As a consequence of enforcing cell cycle progression, th...
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Research Interests: Endocrinology, Genetics, Breast Cancer, Biology, Medicine, and 15 moreGenetic Engineering, Humans, Internal Medicine, Mice, cyclic AMP, Female, Animals, Clinical, Membrane transport, Clinical Sciences, Mouse Model, Mammary gland, Breast Cancer Cells, Breast Neoplasms, and Paediatrics and reproductive medicine
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Research Interests: Chemistry, Medicine, Pregnancy, Humans, Low Dose, and 15 moreReproductive toxicology, bisphenol A, Consensus, North Carolina, Female, Animals, Male, Behavioral Animal Models, Human health, Phenols, Public health systems and services research, Captive Wild Animals, Reproductive, Paediatrics and reproductive medicine, and Pharmacology and pharmaceutical sciences
Research Interests: Risk assessment, Humans, Reproductive toxicology, Endocrine disruptors, Female, and 13 moreAnimals, Male, Risk factors, Phenols, Public health systems and services research, Risk Factors, Risk Assessment, Endocrine Disruptors, Environmental Pollutants, Carcinogen, Breast Neoplasms, Paediatrics and reproductive medicine, and Pharmacology and pharmaceutical sciences
Activin is a well established modulator of male and female reproduction that stimulates the synthesis and secretion of follicle-stimulating hormone. Non-pituitary effects of activin have also been reported, although the paracrine actions... more
Activin is a well established modulator of male and female reproduction that stimulates the synthesis and secretion of follicle-stimulating hormone. Non-pituitary effects of activin have also been reported, although the paracrine actions of this growth factor in several reproductive tissues are not well understood. To identify the paracrine functions of activin during mammary gland morphogenesis and tumor progression, we produced transgenic mice that overexpress follistatin (FST), an intrinsic inhibitor of activin, under control of the mouse mammary tumor virus (MMTV) promoter. Although the MMTV-Fst mice were constructed to assess the role of activin in females, expression of the transgene was also observed in the testes and epididymides of males. While all 17 transgenic founder males exhibited copulatory behavior and produced vaginal plugs in females, only one produced live offspring. In contrast, transgenic females were fertile, permitting expansion of transgenic mouse lines. Ligh...
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Chromosomal instability (CIN), or the dynamic change in chromosome number and composition, has been observed in cancer for decades. Recently, this phenomenon has been implicated as facilitating the acquisition of cancer hallmarks and... more
Chromosomal instability (CIN), or the dynamic change in chromosome number and composition, has been observed in cancer for decades. Recently, this phenomenon has been implicated as facilitating the acquisition of cancer hallmarks and enabling the formation of aggressive disease. Hence, CIN has the potential to serve as a therapeutic target for a wide range of cancers. CIN in cancer often occurs as a result of disrupting key regulators of mitotic fidelity and faithful chromosome segregation. As a consequence of their essential roles in mitosis, dysfunctional centrosomes can induce and maintain CIN. Centrosome defects are common in breast cancer, a heterogeneous disease characterized by high CIN. These defects include amplification, structural defects, and loss of primary cilium nucleation. Recent studies have begun to illuminate the ability of centrosome aberrations to instigate genomic flux in breast cancer cells and the tumor evolution associated with aggressive disease and poor pa...
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Macroautophagy/autophagy is considered to play key roles in tumor cell evasion of therapy and establishment of metastases in breast cancer. High expression of LC3, a residual autophagy marker, in primary breast tumors has been associated... more
Macroautophagy/autophagy is considered to play key roles in tumor cell evasion of therapy and establishment of metastases in breast cancer. High expression of LC3, a residual autophagy marker, in primary breast tumors has been associated with metastatic disease and poor outcome. FIP200/Atg17, a multi-functional pro-survival molecule required for autophagy, has been implicated in brain metastases in experimental models. However, expression of these proteins has not been examined in brain metastases from patients with breast cancer. In this retrospective study, specimens from 44 patients with brain metastases of infiltrating ductal carcinoma of the breast (IDC), unpaired samples from 52 patients with primary IDC (primary-BC) and 16 matched-paired samples were analyzed for LC3 puncta, expression of FIP200/Atg17, and p62 staining. LC3-puncta tumor cells and FIP200/Atg17 expression were detected in greater than 90% of brain metastases but there were considerable intra- and inter-tumor di...
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Research Interests: Psychology and The Breast
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DNA double strand breaks (DSBs) severely disrupt DNA integrity. 53BP1 plays critical roles in determining DSB repair. Whereas the recruitment of 53BP1 to the DSB site is key for its function, recent evidence suggests that 53BP1's... more
DNA double strand breaks (DSBs) severely disrupt DNA integrity. 53BP1 plays critical roles in determining DSB repair. Whereas the recruitment of 53BP1 to the DSB site is key for its function, recent evidence suggests that 53BP1's abundance also plays an important role in DSB repair because recruitment to damage sites will be influenced by protein availability. Initial evidence has pointed to three proteins, the ubiquitin-conjugating enzyme UbcH7, the cysteine protease cathepsin L (CTSL), and the nuclear structure protein lamin A/C, that may impact 53BP1 levels, but the roles of each protein and any interplay between them were unclear. Here we report that UbcH7-dependent degradation plays a major role in controlling 53BP1 levels both under normal growth conditions and during DNA damage. CTSL influenced 53BP1 degradation during DNA damage while having little effect under normal growth conditions. Interestingly, both the protein and the mRNA levels of CTSL were reduced in UbcH7-dep...
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Follistatin (FST) is an intrinsic inhibitor of activin, a member of the transforming growth factor-β superfamily of ligands. The prognostic value of FST and its family members, the follistatin-like (FSTL) proteins, have been studied in... more
Follistatin (FST) is an intrinsic inhibitor of activin, a member of the transforming growth factor-β superfamily of ligands. The prognostic value of FST and its family members, the follistatin-like (FSTL) proteins, have been studied in various cancers. However, these studies, as well as limited functional analyses of the FSTL proteins, have yielded conflicting results on the role of these proteins in disease progression. Furthermore, very few have been focused on FST itself. We assessed whether FST may be a suppressor of tumorigenesis and/or metastatic progression in breast cancer. Using publicly available gene expression data, we examined the expression patterns of FST and INHBA, a subunit of activin, in normal and cancerous breast tissue and the prognostic value of FST in breast cancer metastases, recurrence-free survival, and overall survival. The functional effects of activin and FST on in vitro proliferation, migration, and invasion of breast cancer cells were also examined. FS...
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Research Interests: Cancer, Breast Cancer, Cell Cycle, Regulation, Immunohistochemistry, and 15 moreApoptosis, Signal Transduction, Mice, Female, Animals, Oncogene, Clinical Sciences, Precancerous Conditions, Mammary gland, Disease Progression, DNA binding proteins, Microarray Data, Gene expression profiling, Cumulant, and Transforming Growth Factor
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FOXA1, estrogen receptor α (ERα) and GATA3 independently predict favorable outcome in breast cancer patients, and their expression correlates with a differentiated, luminal tumor subtype. As transcription factors, each functions in the... more
FOXA1, estrogen receptor α (ERα) and GATA3 independently predict favorable outcome in breast cancer patients, and their expression correlates with a differentiated, luminal tumor subtype. As transcription factors, each functions in the morphogenesis of various organs, with ERα and GATA3 being established regulators of mammary gland development. Interdependency between these three factors in breast cancer and normal mammary development has been suggested, but the specific role for FOXA1 is not known. Herein, we report that Foxa1 deficiency causes a defect in hormone-induced mammary ductal invasion associated with a loss of terminal end bud formation and ERα expression. By contrast, Foxa1 null glands maintain GATA3 expression. Unlike ERα and GATA3 deficiency, Foxa1 null glands form milk-producing alveoli, indicating that the defect is restricted to expansion of the ductal epithelium, further emphasizing the novel role for FOXA1 in mammary morphogenesis. Using breast cancer cell lines, we also demonstrate that FOXA1 regulates ERα expression, but not GATA3. These data reveal that FOXA1 is necessary for hormonal responsiveness in the developing mammary gland and ERα-positive breast cancers, at least in part, through its control of ERα expression.