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The advent of sequencing technologies for assessing chromosome conformations has provided a wealth of information on the organization of the 3-dimensional genome and its role in cancer progression. It is now known that changes in chromatin folding and accessibility can promote aberrant activation or repression of transcriptional programs that can drive tumorigenesis and progression in diverse cancers. This includes breast cancer, which comprises several distinct subtypes defined by their unique transcriptomes that dictate treatment response and patient outcomes. Of these, basal-like breast cancer is an aggressive subtype controlled by a pluripotency-enforcing transcriptome. Meanwhile, the more differentiated luminal subtype of breast cancer is driven by an estrogen receptor-dominated transcriptome that underlies its responsiveness to antihormone therapies and conveys improved patient outcomes. Despite the clear differences in molecular signatures, the genesis of each subtype from normal mammary epithelial cells remains unclear. Recent technical advances have revealed key distinctions in chromatin folding and organization between subtypes that could underlie their transcriptomic and, hence, phenotypic differences. These studies also suggest that proteins controlling particular chromatin states may be useful targets for treating aggressive disease. In this review, we explore the current state of understanding of chromatin architecture in breast cancer subtypes and its potential role in defining their phenotypic characteristics., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Activins and inhibins are closely related protein heterodimers with a similar tissue distribution; however, these two complexes have opposing functions in development and disease. Both are secreted cytokine hormones, with activin the primary inducer of downstream signaling cascades and inhibin acting as a rheostat that exquisitely governs activin function. Adding to the complexity of activin signaling, follistatin, a highly glycosylated monomeric protein, binds activin with high affinity and restrains downstream pathway activation but through a mechanism distinct from that of inhibin. These three proteins were first identified as key ovarian hormones in the pituitary-gonadal axis that direct the synthesis and secretion of FSH from the pituitary, hence controlling folliculogenesis. Research during the past 30 years has expanded the roles of these proteins, first by discovering the ubiquitous expression of the trio and then by implicating them in a wide array of biological functions. In concert, these three hormones govern tissue development, homeostasis, and disease in multiple organ systems through diverse autocrine and paracrine mechanisms. In the present study, we have reviewed the actions of activin and its biological inhibitors, inhibin, and follistatin, in mammary gland morphogenesis and cancer., (Copyright © 2019 Endocrine Society.)

Expression of FOXC1, a forkhead box transcription factor, correlates with the human basal-like breast cancer (BLBC) subtype, and functional analyses have revealed its importance for in vitro invasiveness of BLBC cells. Women diagnosed with this breast tumor subtype have a poorer outcome because of the lack of targeted therapies; thus, continued investigation of factors driving these tumors is critical to uncover novel therapeutic targets. Several processes that dictate normal mammary morphogenesis parallel cancer progression, and enforced expression of FOXC1 can induce a progenitor state in more-differentiated mammary epithelial cells. Consequently, evaluating how FOXC1 functions in the normal gland is critical to further understand BLBC biology. Although FOXC1 is well known to control normal development of a number of tissues, its role in the mammary gland has not yet been investigated. Herein, we describe FOXC1 expression patterning in the normal breast, where it is localized to the basal/myoepithelium, suggesting that FOXC1 would be required for normal development. However, mammary glands lacking Foxc1 have no overt defect in ductal outgrowth, alveologenesis, or lineage specification. Of significant interest, we found that expression of FOXC1 is enriched in the normal luminal progenitor population, which is the postulated cell of origin of BLBC. These results indicate that FOXC1 is unnecessary for mammary morphogenesis and that its role in BLBC likely involves processes that are unrelated to cell lineage specification.

Activin is a well-established modulator of male and female reproduction that stimulates the synthesis and secretion of follicle-stimulating hormone. Nonpituitary 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. Light and transmission electron microscopic examination of the transgenic testes and epididymides revealed impairment of fluid resorption and sperm transit in the efferent ducts and initial segment of the epididymis, as indicated by accumulation of fluid and sperm stasis. Consequently, a variety of degenerative lesions were observed in the seminiferous epithelium, such as vacuolation and early stages of mineralization and fibrosis. Sperm collected from the caudae epididymidis of MMTV-Fst males had detached heads and were immotile. Together, these data reveal that activin signaling is essential for normal testicular excurrent duct function and that its blockade impairs fertility. These results also suggest that selective inhibitors of activin signaling may provide a useful approach for the development of male contraceptives without compromising androgen synthesis and actions.