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Estrogen and progesterone receptor (ER, PR) signaling control breast development and impinge on breast carcinogenesis. ER is an established driver of ER + disease but the role of the PR, itself an ER target gene, is debated. We assess the issue in clinically relevant settings by a genetic approach and inject ER + breast cancer cell lines and patient-derived tumor cells to the milk ducts of immunocompromised mice. Such ER + xenografts were exposed to physiologically relevant levels of 17-β-estradiol (E2) and progesterone (P4). We find that independently both premenopausal E2 and P4 levels increase tumor growth and combined treatment enhances metastatic spread. The proliferative responses are patient-specific with MYC and androgen receptor (AR) signatures determining P4 response. PR is required for tumor growth in patient samples and sufficient to drive tumor growth and metastasis in ER signaling ablated tumor cells. Our findings suggest that endocrine therapy may need to be personalized, and that abrogating PR expression can be a therapeutic option. The role of progesterone receptor (PR) and its interplay with estrogen receptor (ER) in breast cancer is controversial. Here, the authors demonstrate that PR can have an ER-independent role in breast cancer growth and metastasis and that its effects are dependent on MYC and androgen receptor signatures.

Invasive lobular carcinoma (ILC) is the most frequent special histological subtype of breast cancer, typically characterized by loss of E‐cadherin. It has clinical features distinct from other estrogen receptor‐positive (ER + ) breast cancers but the molecular mechanisms underlying its characteristic biology are poorly understood because we lack experimental models to study them. Here, we recapitulate the human disease, including its metastatic pattern, by grafting ILC‐derived breast cancer cell lines, SUM‐44 PE and MDA‐MB‐134‐VI cells, into the mouse milk ducts. Using patient‐derived intraductal xenografts from lobular and non‐lobular ER + HER2 − tumors to compare global gene expression, we identify extracellular matrix modulation as a lobular carcinoma cell‐intrinsic trait. Analysis of TCGA patient datasets shows matrisome signature is enriched in lobular carcinomas with overexpression of elastin, collagens, and the collagen modifying enzyme LOXL1 . Treatment with the pan LOX inhibitor BAPN and silencing of LOXL1 expression decrease tumor growth, invasion, and metastasis by disrupting ECM structure resulting in decreased ER signaling. We conclude that LOXL1 inhibition is a promising therapeutic strategy for ILC. Synopsis Intraductal xenografts of invasive lobular carcinoma (ILC) cells faithfully model this breast cancer subtype, and reveal tumor cell intrinsic ECM remodeling as a critical feature of disease progression that can be exploited therapeutically by targeting LOXL1. In vivo ILC models from MDA‐MB134 and SUM44 cell lines are developed and characterized. Additional ILC PDX models are established through the intraductal xenografting approach. Global gene expression profiling reveals ECM remodeling as a key tumor cell intrinsic ILC feature. ILC patient tumors show enhanced ECM production and LOXL1 expression. Inhibition of LOXL1 slows tumor progression in preclinical ILC models. Graphical Abstract Intraductal xenografts of invasive lobular carcinoma (ILC) cells faithfully model this breast cancer subtype, and reveal tumor cell intrinsic ECM remodeling as a critical feature of disease progression that can be exploited therapeutically by targeting LOXL1.

Oestrogen receptor α (ERα) is a transcription factor with ligand-independent and ligand-dependent activation functions (AF)-1 and -2. Oestrogens control postnatal mammary gland development acting on a subset of mammary epithelial cells (MECs), termed sensor cells, which are ERα-positive by immunohistochemistry (IHC) and secrete paracrine factors, which stimulate ERα-negative responder cells. Here we show that deletion of AF-1 or AF-2 blocks pubertal ductal growth and subsequent development because both are required for expression of essential paracrine mediators. Thirty percent of the luminal cells are ERα-negative by IHC but express Esr1 transcripts. This low level ERα expression through AF-2 is essential for cell expansion during puberty and growth-inhibitory during pregnancy. Cell-intrinsic ERα is not required for cell proliferation nor for secretory differentiation but controls transcript levels of cell motility and cell adhesion genes and a stem cell and epithelial mesenchymal transition (EMT) signature identifying ERα as a key regulator of mammary epithelial cell plasticity. Oestrogen receptors α (ERα) are expressed in a subset of mammary epithelial cells. Here, the authors identify cells with low-ERα protein levels and show that distinct cell populations have distinct requirements for the AF1 and AF2 domains of the ERα, and ERα acts in a biphasic manner dependent on developmental stage.

Hormonal contraception exposes women to synthetic progesterone receptor (PR) agonists, progestins, and transiently increases breast cancer risk. How progesterone and progestins affect the breast epithelium is poorly understood because we lack adequate models to study this. We hypothesized that individual progestins differentially affect breast epithelial cell proliferation and hence breast cancer risk. Using mouse mammary tissue ex vivo, we show that testosterone‐related progestins induce the PR target and mediator of PR signaling‐induced cell proliferation receptor activator of NF‐κB ligand (Rankl), whereas progestins with anti‐androgenic properties in reporter assays do not. We develop intraductal xenografts of human breast epithelial cells from 36 women, show they remain hormone‐responsive and that progesterone and the androgenic progestins, desogestrel, gestodene, and levonorgestrel, promote proliferation but the anti‐androgenic, chlormadinone, and cyproterone acetate, do not. Prolonged exposure to androgenic progestins elicits hyperproliferation with cytologic changes. Androgen receptor inhibition interferes with PR agonist‐ and levonorgestrel‐induced RANKL expression and reduces levonorgestrel‐driven cell proliferation. Thus, different progestins have distinct biological activities in the breast epithelium to be considered for more informed choices in hormonal contraception. Synopsis Hormonal contraception exposes women to different progestins in conjunction or without estrogen. The androgenic properties of progestins determine their biological activity in the breast epithelium and reveal an unexpected role for AR activity in breast epithelial cell proliferation. Androgenic progestins induce expression of Rankl, an important mediator of PR signaling‐induced cell proliferation in the mammary epithelium, whereas anti‐androgenic progestins fail to do so. AR activity is required for the induction of Rankl transcripts. Human breast epithelial cells engraft and proliferate in mouse milk ducts maintaining nuclear hormone receptor expression and hormone responsiveness. Androgenic but not anti‐androgenic progestins promote cell proliferation in xenografted human breast epithelia. Prolonged exposure to androgenic progestins causes hyperproliferation and cytological changes associated with early premalignant lesions in xenografted human breast epithelia. Graphical Abstract Hormonal contraception exposes women to different progestins in conjunction or without estrogen. The androgenic properties of progestins determine their biological activity in the breast epithelium and reveal an unexpected role for AR activity in breast epithelial cell proliferation.

To improve preclinical studies and their translation, patient-derived xenografts (PDXs) are increasingly used. They have human-specific tumor characteristics and reflect intra and inter-tumor heterogeneity. However, the endocrine milieu differs between humans and host mice. In light of sex-specific cancer biology and a rise in endocrine-related cancers there is an urgent need to correctly reflect the hormonal milieu in PDX models. We show that female mice of NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ (NSG) strain widely used for PDXs has 17-β-estradiol (E2) and testosterone (T) levels comparable to C57Bl6 females but higher progesterone (P4) levels. E2 levels are comparable, T levels are lower and P4 levels higher than those observed in postmenopausal women. Ovariectomy increases T to levels observed in postmenopausal women. Subcutaneous E2 and combined E2/P4 silicon pellets provide NSG females with premenopausal ovarian hormone levels. These procedures humanize the endocrine environment of experimental animals, improving PDX relevance in women’s health-related research.

Patient-derived xenograft (PDX) models of a growing spectrum of cancers are rapidly supplanting long-established traditional cell lines as preferred models for conducting basic and translational preclinical research. In breast cancer, to complement the now curated collection of approximately 45 long-established human breast cancer cell lines, a newly formed consortium of academic laboratories, currently from Europe, Australia, and North America, herein summarizes data on over 500 stably transplantable PDX models representing all three clinical subtypes of breast cancer (ER+, HER2+, and “Triple-negative” (TNBC)). Many of these models are well-characterized with respect to genomic, transcriptomic, and proteomic features, metastatic behavior, and treatment response to a variety of standard-of-care and experimental therapeutics. These stably transplantable PDX lines are generally available for dissemination to laboratories conducting translational research, and contact information for each collection is provided. This review summarizes current experiences related to PDX generation across participating groups, efforts to develop data standards for annotation and dissemination of patient clinical information that does not compromise patient privacy, efforts to develop complementary data standards for annotation of PDX characteristics and biology, and progress toward “credentialing” of PDX models as surrogates to represent individual patients for use in preclinical and co-clinical translational research. In addition, this review highlights important unresolved questions, as well as current limitations, that have hampered more efficient generation of PDX lines and more rapid adoption of PDX use in translational breast cancer research.

Estrogen receptor alpha positive (ER+) or luminal breast cancers were notoriously difficult to establish as patient-derived xenografts (PDXs). We and others recently demonstrated that the microenvironment is critical for ER+ tumor cells; by grafting them into milk ducts >90% take rates are achieved and many features of the human disease are recapitulated. This intra-ductal (ID) approach holds promise for personalized medicine, yet human and murine stroma are organized differently and this and other species specificities may limit the value of this model. Here, we analyzed 21 ER+ ID-PDXs histopathologically. We find that ID-PDXs vary in extent and define four histopathological patterns: columnar, lobular, in situ, and invasive, which occur in pure and combined forms. The ID-PDXs replicate earlier stages of tumor development than their clinical counterparts. Micrometastases are already detected when lesions appear in situ. Tumor extent, histopathological patterns, and metastatic load correlate with biological properties of their tumors of origin. Our findings add evidence to the validity of the intraductal model for in vivo studies of ER+ BC and raise the intriguing possibility that tumor cell dissemination may occur earlier than currently thought.

Abstract Disclosure: G. Scozia: None. D. Menghini: None. D. Fintini: None. S. Cianfarani: None. V. Russo: None. M. Mainardi: None. N. Gianni: None. G. Furini: None. G. Scabia: None. M. Maffei: None. M. Manco: None. Background: In pediatric obesity, altered energy regulation and impaired inhibitory control over food intake are linked to dysfunction in the dorsolateral prefrontal cortex (DLPFC). Lifestyle interventions can potentially restore these brain-metabolic pathways. Leptin, brain-derived neurotrophic factor (BDNF), and eotaxin (CCL11), a chemokine involved in immune signaling, may modulate neural responses to metabolic challenges. Objective: To assess the impact of an 8-week intensive health behavioral treatment (IHBT) on DLPFC activation during oral glucose tolerance testing (OGTT), and to explore the relationship with insulin sensitivity and circulating levels of leptin, BDNF and eotaxin in children with obesity. Methods: Twenty-seven children with obesity (mean age 11 years) underwent functional near-infrared spectroscopy (fNIRS) during OGTT at baseline (T0) and post-IHBT (T1). The IHBT included healthy diet, structured physical activity, and cognitive training. Changes in cerebral blood flow (total Hb, tHb) and oxygenated hemoglobin (O₂Hb) were measured in the DLPFC. Insulin sensitivity was assessed via the Matsuda Index and HOMA-IR; serum eotaxin, leptin, and BDNF levels were also measured by commercial assays. Results: After IHBT, there was a significant increase in bilateral DLPFC activation during OGTT:Left DLPFC: ΔO₂Hb ↑, p < 0.01Right DLPFC: ΔO₂Hb ↑, p < 0.05ΔtHb bilateral ↑, indicating enhanced cortical perfusion Improvement in DLPFC activity correlated with metabolic indices:Positive correlation with Matsuda Index (r = 0.54, p < 0.01)Negative correlation with HOMA-IR (r = -0.47, p < 0.05)Left DLPFC activation at T1 showed sex-related differences, with greater increase in males (p < 0.05) Baseline eotaxin levels were positively associated with DLPFC activation changes at T1 (r = 0.41, p < 0.05), while leptin and BDNF showed no significant associations. Conclusion: An 8-week lifestyle intervention significantly enhanced DLPFC activation during glucose challenge, suggesting improved neural regulation of food-related behavior in children with obesity. The association with eotaxin implicates a potential neuroimmune mechanism whereby inflammatory signaling may influence prefrontal responsiveness to metabolic inputs. Eotaxin may serve as a biomarker of neuroplastic adaptation to behavioral interventions targeting obesity. Presentation: Monday, July 14, 2025