Inman, J. L., Robertson, C., Mott, J. D. & Bissell, M. J. Mammary gland development: cell fate specification, stem cells and the microenvironment. Development 142, 1028–1042 (2015).
Google Scholar
Fu, N. Y., Nolan, E., Lindeman, G. J. & Visvader, J. E. Stem cells and the differentiation hierarchy in mammary gland development. Physiol Rev 100, 489–523 (2020).
Google Scholar
Tiede, B. & Kang, Y. From milk to malignancy: the role of mammary stem cells in development, pregnancy and breast cancer. Cell Res. 21, 245–257 (2011).
Google Scholar
Wiseman, B. S. & Werb, Z. Stromal effects on mammary gland development and breast cancer. Science 296, 1046–1049 (2002).
Google Scholar
Sternlicht, M. D., Kouros-Mehr, H., Lu, P. & Werb, Z. Hormonal and local control of mammary branching morphogenesis. Differentiation 74, 365–381 (2006).
Google Scholar
Parmar, H. & Cunha, G. R. Epithelial–stromal interactions in the mouse and human mammary gland in vivo. Endocr Relat Cancer 11, 437–458 (2004).
Google Scholar
The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012).
Visvader, J. E. & Clevers, H. Tissue-specific designs of stem cell hierarchies. Nat Cell Biol 18, 349–355 (2016).
Google Scholar
Lloyd-Lewis, B., Harris, O. B., Watson, C. J. & Davis, F. M. Mammary stem cells: premise, properties, and perspectives. Trends Cell Biol. 27, 556–567 (2017).
Google Scholar
Visvader, J. E. Keeping abreast of the mammary epithelial hierarchy and breast tumorigenesis. Genes Dev 23, 2563–2577 (2009).
Google Scholar
Gray, G. K. et al. Defining breast epithelial cell types in the single-cell era. Dev Cell 60, 2218–2236 (2025).
Google Scholar
Shackleton, M. et al. Generation of a functional mammary gland from a single stem cell. Nature 439, 84–88 (2006).
Google Scholar
Stingl, J. et al. Purification and unique properties of mammary epithelial stem cells. Nature 439, 993–997 (2006).
Google Scholar
Deome, K. B., Faulkin, L. J. Jr., Bern, H. A. & Blair, P. B. Development of mammary tumors from hyperplastic alveolar nodules transplanted into gland-free mammary fat pads of female C3H mice. Cancer Res 19, 515–520 (1959).
Google Scholar
Daniel, C. W. et al. The in vivo life span of normal and preneoplastic mouse mammary glands: a serial transplantation study. Proc. Natl. Acad. Sci. USA 61, 53–60 (1968).
Google Scholar
Prater, M. D. et al. Mammary stem cells have myoepithelial cell properties. Nat Cell Biol 16, 942–950 (2014).
Google Scholar
Sahu, S. et al. Spatiotemporal modulation of growth factors directs the generation of multilineage mouse embryonic stem cell-derived mammary organoids. Dev Cell 59, 175–186.e8 (2024).
Google Scholar
Rosenbluth, J. M. et al. Organoid cultures from normal and cancer-prone human breast tissues preserve complex epithelial lineages. Nat Commun 11, 1711 (2020).
Google Scholar
Kretzschmar, K. & Watt, F. M. Lineage tracing. Cell 148, 33–45 (2012).
Google Scholar
Van Keymeulen, A. et al. Lineage-restricted mammary stem cells sustain the development, homeostasis, and regeneration of the estrogen receptor positive lineage. Cell Rep. 20, 1525–1532 (2017).
Google Scholar
Elias, S., Morgan, M. A., Bikoff, E. K. & Robertson, E. J. Long-lived unipotent Blimp1-positive luminal stem cells drive mammary gland organogenesis throughout adult life. Nat Commun 8, 1714 (2017).
Google Scholar
Rios, A. C., Fu, N. Y., Lindeman, G. J. & Visvader, J. E. In situ identification of bipotent stem cells in the mammary gland. Nature 506, 322–327 (2014).
Google Scholar
Wang, D. et al. Identification of multipotent mammary stem cells by protein C receptor expression. Nature 517, 81–84 (2015).
Google Scholar
Chakrabarti, R. et al. Notch ligand Dll1 mediates cross-talk between mammary stem cells and the macrophageal niche. Science 360, 6396 (2018).
Davis, F. M. et al. Single-cell lineage tracing in the mammary gland reveals stochastic clonal dispersion of stem/progenitor cell progeny. Nat Commun 7, 13053 (2016).
Google Scholar
Beumer, J. & Clevers, H. Hallmarks of stemness in mammalian tissues. Cell Stem Cell 31, 7–24 (2024).
Google Scholar
Lin, Z. et al. Distinct mammary stem cells orchestrate long-term homeostasis of adult mammary gland. Cell Discov 11, 39 (2025).
Google Scholar
Sleeman, K. E. et al. Dissociation of estrogen receptor expression and in vivo stem cell activity in the mammary gland. J Cell Biol 176, 19–26 (2007).
Google Scholar
Rodilla, V. et al. Luminal progenitors restrict their lineage potential during mammary gland development. PLoS Biol 13, e1002069 (2015).
Google Scholar
Gusterson, B. Do ‘basal-like’ breast cancers really exist? Nat Rev Cancer 9, 128–134 (2009).
Google Scholar
Lee, E., Piranlioglu, R., Wicha, M. S. & Korkaya, H. Plasticity and potency of mammary stem cell subsets during mammary gland development. Int J Mol Sci 20, 2357 (2019).
Nolan, E., Lindeman, G. J. & Visvader, J. E. Deciphering breast cancer: from biology to the clinic. Cell 186, 1708–1728 (2023).
Google Scholar
Weigelt, B. & Reis-Filho, J. S. Histological and molecular types of breast cancer: is there a unifying taxonomy? Nat Rev Clin. Oncol. 6, 718–730 (2009).
Google Scholar
Prat, A. et al. Molecular features and survival outcomes of the intrinsic subtypes within HER2-positive breast cancer. J Natl Cancer Inst 106, 152 (2014).
Lo, P. K. et al. CD49f and CD61 identify Her2/neu-induced mammary tumor-initiating cells that are potentially derived from luminal progenitors and maintained by the integrin-TGFbeta signaling. Oncogene 31, 2614–2626 (2012).
Google Scholar
Molyneux, G. et al. BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell 7, 403–417 (2010).
Google Scholar
Radler, P. D. et al. Highly metastatic claudin-low mammary cancers can originate from luminal epithelial cells. Nat Commun 12, 3742 (2021).
Google Scholar
Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J. & Clarke, M. F. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100, 3983–3988 (2003).
Google Scholar
Celia-Terrassa, T. & Kang, Y. Distinctive properties of metastasis-initiating cells. Genes Dev 30, 892–908 (2016).
Google Scholar
Cicalese, A. et al. The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells. Cell 138, 1083–1095 (2009).
Google Scholar
Kaur, R. P., Vasudeva, K., Kumar, R. & Munshi, A. Role of p53 gene in breast cancer: focus on mutation spectrum and therapeutic strategies. Curr Pharm Des 24, 3566–3575 (2018).
Google Scholar
Lado-Fernández, P. et al. Transcriptional repression of SOX2 by p53 in cancer cells regulates cell identity and migration. Int J Cancer 157, 980–992 (2025).
Google Scholar
Santoro, A. et al. p53 loss in breast cancer leads to Myc activation, increased cell plasticity, and expression of a mitotic signature with prognostic value. Cell Rep 26, 624–638.e8 (2019).
Google Scholar
Ghatak, D., Das Ghosh, D. & Roychoudhury, S. Cancer stemness: p53 at the wheel. Front Oncol 10, 604124 (2020).
Google Scholar
Li, Y. et al. p63: a crucial player in epithelial stemness regulation. Oncogene 42, 3371–3384 (2023).
Google Scholar
Chakrabarti, R. et al. ΔNp63 promotes stem cell activity in mammary gland development and basal-like breast cancer by enhancing Fzd7 expression and Wnt signalling. Nat Cell Biol 16, 1004–1015 (2014).
Google Scholar
Sadu Murari, L. S. et al. p63: A master regulator at the crossroads between development, senescence, aging, and cancer. Cells 14, 43 (2025).
Romano, R. A. et al. ΔNp63 knockout mice reveal its indispensable role as a master regulator of epithelial development and differentiation. Development 139, 772–782 (2012).
Google Scholar
Su, X. et al. TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs. Nature 467, 986–990 (2010).
Google Scholar
Memmi, E. M. et al. p63 sustains self-renewal of mammary cancer stem cells through regulation of Sonic Hedgehog signaling. Proc Natl Acad Sci USA 112, 3499–3504 (2015).
Google Scholar
Celià-Terrassa, T. Mammary stem cells and breast cancer stem cells: molecular connections and clinical implications. Biomedicines 6, 50 (2018).
Google Scholar
Guo, W. et al. Slug and Sox9 cooperatively determine the mammary stem cell state. Cell 148, 1015–1028 (2012).
Google Scholar
Mani, S. A. et al. The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715 (2008).
Google Scholar
Yang, J. et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117, 927–939 (2004).
Google Scholar
Domenici, G. et al. A Sox2–Sox9 signalling axis maintains human breast luminal progenitor and breast cancer stem cells. Oncogene 38, 3151–3169 (2019).
Google Scholar
Dravis, C. et al. Sox10 regulates stem/progenitor and mesenchymal cell states in mammary epithelial cells. Cell Reports 12, 2035–2048 (2015).
Google Scholar
Celià-Terrassa, T. et al. Normal and cancerous mammary stem cells evade interferon-induced constraint through the miR-199a–LCOR axis. Nat Cell Biol 19, 711–723 (2017).
Google Scholar
Roth, M. J. & Moorehead, R. A. The miR-200 family in normal mammary gland development. BMC Dev Biol 21, 12 (2021).
Google Scholar
Korpal, M. et al. Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization. Nat Med 17, 1101–1108 (2011).
Google Scholar
Sharrocks, A. D. The ETS-domain transcription factor family. Nat Rev Mol Cell Biol 2, 827–837 (2001).
Google Scholar
Chakrabarti, R. et al. Elf5 inhibits the epithelial–mesenchymal transition in mammary gland development and breast cancer metastasis by transcriptionally repressing Snail2. Nat Cell Biol. 14, 1212–1222 (2012).
Google Scholar
Zeng, Y. A. & Nusse, R. Wnt proteins are self-renewal factors for mammary stem cells and promote their long-term expansion in culture. Cell Stem Cell 6, 568–577 (2010).
Google Scholar
Brisken, C. et al. Essential function of Wnt-4 in mammary gland development downstream of progesterone signaling. Genes Dev. 14, 650–654 (2000).
Google Scholar
Rajaram, R. D. et al. Progesterone and Wnt4 control mammary stem cells via myoepithelial crosstalk. EMBO J. 34, 641–652 (2015).
Google Scholar
Cai, C. et al. R-spondin1 is a novel hormone mediator for mammary stem cell self-renewal. Genes Dev 28, 2205–2218 (2014).
Google Scholar
Wend, P. et al. WNT10B/β-catenin signalling induces HMGA2 and proliferation in metastatic triple-negative breast cancer. EMBO Mol. Med. 5, 264–279 (2013).
Google Scholar
Liu, W., Wu, T., Dong, X. & Zeng, Y. A. Neuropilin-1 is upregulated by Wnt/β-catenin signaling and is important for mammary stem cells. Sci Rep 7, 10941 (2017).
Google Scholar
Chen, W. et al. Mammary development and breast cancer: a notch perspective. J Mammary Gland Biol Neoplasia 26, 309–320 (2021).
Google Scholar
Shostak, K. & Chariot, A. NF-κB, stem cells and breast cancer: the links get stronger. Breast Cancer Res 13, 214 (2011).
Google Scholar
Tanaka, H. et al. The Hedgehog signaling pathway plays an essential role in maintaining the CD44+CD24−/low subpopulation and the side population of breast cancer cells. Anticancer Res 29, 2147–2157 (2009).
Google Scholar
Park, J. H., Shin, J. E. & Park, H. W. The role of hippo pathway in cancer stem cell biology. Mol Cells 41, 83–92 (2018).
Google Scholar
Temple, A. E. & Walker, S. R. The roles of STAT3 and STAT5 in breast cancer. Cancers 17, 1781 (2025).
Google Scholar
Avagliano, A. et al. Influence of fibroblasts on mammary gland development, breast cancer microenvironment remodeling, and cancer cell dissemination. Cancers 12, 1697 (2020).
Google Scholar
Page-McCaw, A., Ewald, A. J. & Werb, Z. Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol 8, 221–233 (2007).
Google Scholar
Lee, E. et al. CXCR4+ mammary gland macrophageal niche promotes tumor initiating cell activity and immune suppression during tumorigenesis. Nat Commun 16, 4854 (2025).
Google Scholar
Zhou, Y. et al. Macrophages maintain mammary stem cell activity and mammary homeostasis via TNF-α-PI3K-Cdk1/Cyclin B1 axis. npj Regener Med 8, 23 (2023).
Google Scholar
Liu, C. et al. Niche inflammatory signals control oscillating mammary regeneration and protect stem cells from cytotoxic stress. Cell Stem Cell 31, 89–105.e6 (2024).
Google Scholar
Verona, F. et al. Cancer stem cells and tumor-associated macrophages as mates in tumor progression: mechanisms of crosstalk and advanced bioinformatic tools to dissect their phenotypes and interaction. Front Immunol 16, 1529847 (2025).
Google Scholar
Plaks, V. et al. Adaptive immune regulation of mammary postnatal organogenesis. Dev Cell 34, 493–504 (2015).
Google Scholar
Chakravarti, M. et al. Terminally exhausted CD8+ T cells resistant to PD-1 blockade promote generation and maintenance of aggressive cancer stem cells. Cancer Res 83, 1815–1833 (2023).
Google Scholar
Wu, Q. et al. Cancer-associated adipocytes: key players in breast cancer progression. J Hematol Oncol. 12, 95 (2019).
Google Scholar
Callihan, E. B. et al. Postpartum diagnosis demonstrates a high risk for metastasis and merits an expanded definition of pregnancy-associated breast cancer. Breast Cancer Res. Treat 138, 549–559 (2013).
Google Scholar
Lambe, M. et al. Transient increase in the risk of breast cancer after giving birth. N Engl J Med 331, 5–9 (1994).
Google Scholar
Whiteman, M. K. et al. Reproductive history and mortality after breast cancer diagnosis. Obstet Gynecol. 104, 146 (2004).
Google Scholar
Johansson, A. L. V. & Stensheim, H. Epidemiology of pregnancy-associated breast cancer. Adv Exp Med Biol 1252, 75–79 (2020).
Proussaloglou, E. M., Blanco, L. Z. & Siziopikou, K. P. Updates in the pathology of pregnancy associated breast cancer (PABC). Pathol Res. Pract. 244, 154413 (2023).
Google Scholar
Martinson, H. A., Jindal, S., Durand-Rougely, C., Borges, V. F. & Schedin, P. Wound healing-like immune program facilitates postpartum mammary gland involution and tumor progression. Int J Cancer 136, 1803–1813 (2015).
Google Scholar
Schedin, P., Mitrenga, T., McDaniel, S. & Kaeck, M. Mammary ECM composition and function are altered by reproductive state. Mol Carcinog 41, 207–220 (2004).
Google Scholar
Elder, A. M. et al. Semaphorin 7A promotes macrophage-mediated lymphatic remodeling during postpartum mammary gland involution and in breast cancer. Cancer Res. 78, 6473–6485 (2018).
Google Scholar
Chen, C.-H. et al. Characterization of the tumor immune microenvironment in pregnancy-associated breast cancer through multiplex immunohistochemistry and transcriptome analyses. Breast Cancer Res. 27, 154 (2025).
Google Scholar
Peña-Enríquez, R. et al. Molecular characterization of pregnancy-associated breast cancer and insights on timing from GEICAM-EMBARCAM study. npj Breast Cancer 11, 12 (2025).
Google Scholar
Elder, A. M., Stoller, A. R., Black, S. A. & Lyons, T. R. Macphatics and PoEMs in postpartum mammary development and tumor progression. J Mammary Gland Biol. Neoplasia 25, 103–113 (2020).
Google Scholar
Lefrère, H. et al. Poor outcome in postpartum breast cancer patients is associated with distinct molecular and immunologic features. Clin Cancer Res. 29, 3729–3743 (2023).
Google Scholar
Ogony, J. W. et al. A STAT1–GBP1 axis modulates epithelial proliferation in postpartum breast tissue by repressing CDKI expression. Breast Cancer Res. 27, 162 (2025).
Google Scholar
Feigman, M. J. et al. Pregnancy reprograms the epigenome of mammary epithelial cells and blocks the development of premalignant lesions. Nat Commun 11, 2649 (2020).
Google Scholar
Lin, J. et al. Changes in the mammary gland during aging and its links with breast diseases. Acta Biochim Biophys Sin (Shanghai) 55, 1001–1019 (2023).
Li, C. M. et al. Aging-associated alterations in mammary epithelia and stroma revealed by single-cell RNA sequencing. Cell Rep 33, 108566 (2020).
Google Scholar
Yan, P. et al. Midkine as a driver of age-related changes and increase in mammary tumorigenesis. Cancer Cell 42, 1936–1954.e9 (2024).
Google Scholar
Angarola, B. L. et al. Comprehensive single-cell aging atlas of healthy mammary tissues reveals shared epigenomic and transcriptomic signatures of aging and cancer. Nat Aging 5, 122–143 (2025).
Google Scholar
Sayaman, R. W. et al. Luminal epithelial cells integrate variable responses to aging into stereotypical changes that underlie breast cancer susceptibility. eLife 13, e95720 (2024).

