年龄相关的小叶复旧与乳腺癌

随着年龄增长,女性乳腺实质逐渐出现萎缩、退化甚至消失,这一生理性的过程称为年龄相关的小叶复旧.小叶复旧是不可逆的、系统性的个体化过程,与包括乳腺密度在内诸多乳腺癌危险因素密切相关,并被认为与乳腺癌的患病风险有关,但其具体机制尚不明确.     

A Mouse Mammary Gland Involution mRNA Signature Identifies Biological Pathways Potentially Associated with Breast Cancer Metastasis

Mouse mammary gland involution resembles a wound healing response with suppressed inflammation. Wound healing and inflammation are also associated with tumour development, and a ‘wound-healing’ gene expression signature can predict metastasis formation and survival. Recent studies have shown that an involuting mammary gland stroma can promote metastasis. It could therefore be hypothesised that gene expression signatures from an involuting mouse mammary gland may provide new insights into the physiological pathways that promote breast cancer progression. Indeed, using the HOPACH clustering method, the human orthologues of genes that were differentially regulated at day 3 of mammary gland involution and showed prolonged expression throughout the first 4 days of involution distinguished breast cancers in the NKI 295 breast cancer dataset with low and high metastatic activity. Most strikingly, genes associated with copper ion homeostasis and with HIF-1 promoter binding sites were the most over-represented, linking this signature to hypoxia. Further, six out of the ten mRNAs with strongest up-regulation in cancers with poor survival code for secreted factors, identifying potential candidates that may be involved in stromal/matrix-enhanced metastasis formation/breast cancer development. This method therefore identified biological processes that occur during mammary gland involution, which may be critical in promoting breast cancer metastasis that could form a basis for future investigation, and supports a role for copper in breast cancer development. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. An erratum to this article can be found at     

Do inflammatory cells participate in mammary gland involution?

The processes by which the involuting mammary gland clears residual milk and milk fat, as well as apoptotic cells, have gone largely unstudied in the modern literature. Here we review the evidence for and against the involvement of professional phagocytes of hematopoetic lineage in this process. Additionally we present evidence that mammary epithelial cells themselves are capable of phagocytosis and may be responsible for the majority of apoptotic cell and residual milk clearance during murine involution. In this scheme these cells regulate their cytokine production in response to apoptotic cells in a manner similar to other cells, including macrophages. The ensuing model describes a process of involution that actively suppresses an inflammatory response in the gland, allowing for effective tissue remodeling and damage prevention.     

Differentiation of the Mammary Epithelial Cell during Involution: Implications for Breast Cancer

That milk secretion is not the final differentiated state of the mammary alveolar cells is a relatively new concept. Recent work has suggested that secreting, mammary epithelial cells (MECs) have another function to perform before they undergo cell death in the involuting mammary gland. That is, they help in the final clearance and breakdown of their neighboring cells (and likely residual milk as well.) They become, for a short time, amateur phagocytes, or efferocytes, and then are believed to die and be cleared themselves. Although relatively little study has been made of this change in the functional state of the MEC, nevertheless we may speculate from the involution literature, and extend findings from other systems of apoptotic cell clearance, on some of the mechanisms involved. And with the finding that involution may represent a unique susceptibility window for the progression of metastatic breast cancer, we may suggest areas for future research along these lines as well. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Microenvironment of the Involuting Mammary Gland Mediates Mammary Cancer Progression

Breast cancer diagnosed after a completed pregnancy has higher metastatic potential and therefore a much poorer prognosis. We hypothesize that following pregnancy the process of mammary gland involution, which returns the gland to its pre-pregnant state, co-opts some of the programs of wound healing. The pro-inflammatory milieu that results, while physiologically normal, promotes tumor progression. In this review, the similarities between mammary gland involution after cessation of milk-production and pathological tissue remodeling are discussed in light of emerging data demonstrating a role for pathological tissue remodeling in cancer.     

Growth Factors, Apoptosis, and Survival of Mammary Epithelial Cells

Programmed cell death (apoptosis) occursregularly during normal growth and development of themammary gland. One of the most dramatic examples ofapoptosis is evident during the remodeling of the breast that accompanies postlactational involution.Transgenic mouse models have demonstrated thatoverexpression of polypeptides such as transforminggrowth factor alpha (TGF)³ and insulinlike growth factor I (IGF-I) can block this remodeling, suggestingthat these growth factors may be acting as survivalfactors for the mammary epithelium. In contrast,transgenic mice that overexpress the growth inhibitor transforming growth factor beta (TGF-)show increased apoptosis in the mammary epitheliumthroughout mammary development, suggestive of amechanism working to counterbalance the survivalfactors. Experiments with mammary epithelial cell lines cultured invitro have confirmed that these growth factors canindeed regulate apoptosis and survival in mammaryepithelial cells; EGF, IGF-I, and basic fibroblastgrowth factor (bFGF) act as survival factors formammary epithelial cells, while TGF- induces theirdeath. In breast cancer, cytotoxic drugs and hormoneablation increase the expression of TGF-, which may function to induce cell death by eitherparacrine or autocrine mechanisms. Lastly, although ithas very limited expression in the breast, TNFhas been shown to be effective in the rapid, direct induction of cell death in breast cancer celllines. Together, these studies describe a complexdynamic pattern of cell death-inducing and survivalfactors that promote the development of the maturemammary gland and that rapidly remodel the tissue afterlactation.     

Bcl-2 Gene Family and Related Proteins in Mammary Gland Involution and Breast Cancer

The Bcl-2 gene family regulates tissuedevelopment and tissue homeostasis through the interplayof survival and death factors. Family members arecharacterized as either pro-apoptotic or anti-apoptotic, depending on cellular context. In addition toits anti-apoptotic effect, Bcl-2 also inhibitsprogression through the cell cycle. Functionalinteractions between family members as well as bindingto other cellular proteins modulate their activities.Mammary gland tissue, similar to many other tissues,expresses a number of different Bcl-2 relativesincluding bclx, bax, bak, bad, bcl-w, bfl-1, bcl-2 aswell as the bcl-2 binding protein Bag-1. Bcl-2 isexpressed in the nonpregnant mammary gland and earlypregnancy. In contrast, expression of bcl-x and baxcontinues through late pregnancy, is down-regulated during lactation, and upregulated with thestart of involution. Bak, bad, bcl-w, and bfl-1 are alsoup-regulated during involution. The specific roles ofindividual gene products are investigated using dominant gain of function and loss of functionmice. Finally, different Bcl-2 family members arecommonly over- or under-expressed in human breastcancers. Bcl-2 expression in human breast cancers hasbeen associated with a good prognosis, whiledecreased Bax expression has been linked to poorclinical outcome. Understanding the role Bcl-2 familymembers play in regulating mammary epithelial cellsurvival is salient to both normal mammary glandphysiology and the development of new therapeuticapproaches to breast cancer.     

Mammary Gland Involution as an Immunotherapeutic Target for Postpartum Breast Cancer

Postpartum mammary gland involution has been identified as tumor-promotional and is proposed to contribute to the increased rates of metastasis and poor survival observed in postpartum breast cancer patients. In rodent models, the involuting mammary gland microenvironment is sufficient to induce enhanced tumor cell growth, local invasion, and metastasis. Postpartum involution shares many attributes with wound healing, including upregulation of genes involved in immune responsiveness and infiltration of tissue by immune cells. In rodent models, treatment with non-steroidal anti-inflammatory drugs (NSAIDs) ameliorates the tumor-promotional effects of involution, consistent with the immune milieu of the involuting gland contributing to tumor promotion. Currently, immunotherapy is being investigated as a means of breast cancer treatment with the purpose of identifying ways to enhance anti-tumor immune responses. Here we review evidence for postpartum mammary gland involution being a uniquely defined ‘hot-spot’ of pro-tumorigenic immune cell infiltration, and propose that immunotherapy should be explored for prevention and treatment of breast cancers that arise in this environment.     

A Developmental Atlas of Rat Mammary Gland Histology

The mammary gland is a dynamic tissue that undergoes epithelial expansion and invasion during puberty and cycles of branching and lobular morphogenesis, secretory differentiation, and regression during pregnancy, lactation, and involution. The alteration in the mammary gland epithelium during its postnatal differentiation is accompanied by changes in the multiple stromal cell types present in this complex tissue. The postnatal plasticity of the epithelium, endothelium, and stromal cells of the mammary gland may contribute to its susceptibility to carcinogenesis. The purpose of this review is to assist researchers in recognizing histological changes in the epithelium and stroma of the rat mammary gland throughout development.     

Role of Prolactin and Vasoinhibins in the Regulation of Vascular Function in Mammary Gland

The formation of new blood vessels has become a major focus of mammary gland research stimulated by the therapeutic opportunities of controlling angiogenesis in breast cancer. Normal growth and involution of the mammary gland are profoundly affected by the expansion and regression of blood vessels, whereas dysregulation of angiogenesis is characteristic of breast cancer growth and metastasis. Prolactin stimulates the growth and differentiation of the mammary gland under normal conditions, but its role in breast cancer is controversial. Its action is complicated by the fact that prolactin itself is angiogenic, but proteases cleave prolactin to generate vasoinhibins, a family of peptides that act on endothelial cells to suppress angiogenesis and vasodilation and to promote apoptosis-mediated vascular regression. This review summarizes our current knowledge about the vascular effects of prolactin and the generation and action of vasoinhibins, and discusses their possible contribution to the regulation of blood vessels in the normal and malignant mammary gland.     

Local production of estrogen via aromatase and estrone sulfatase in breast cancer tissue

The activities of aromatase and estrone sulfatase which are important enzymes involved in the local production of estrogen in breast cancer tissue were measured to examine their availability in endocrine therapy and their clinical significance. The materials obtained were breast cancer tissue, noncancerous mammary gland and breast fat tissue from twenty eight patients with breast cancer, and mammary gland tissue from eight patients with benign breast disease. After centrifugation of homogenized tissue at 1000 X g, the supernatant of breast cancer tissue or mammary gland and the subnatant of breast fat tissue were used as enzyme sources. Aromatase activity was measured by 3H2O release assay using (1 beta-3H) androstenedione as the substrate, while estrone sulfatase activity was estimated from the conversion rate of (6,7-3H)estrone-3-sulfate to estrone. Aromatase activities were 25.1 +/- 12.4 (mean +/- S.D.) fmol/mg protein/h in twenty seven breast cancer tissue specimens, 11.0 +/- 6.1 fmol/mg protein/h in sixteen noncancerous mammary gland tissue specimens, 9.3 +/- 10.0 fmol/mg protein/h in twenty seven breast fat tissue specimens, and 7.7 +/- 5.5 fmol/mg protein/h in eight mammary gland tissue specimens from patients with benign breast disease. The aromatase activity in breast cancer tissue was significantly higher than that in noncancerous mammary gland, breast fat tissue and benign breast lesions (p less than 0.001). Estrone sulfatase activity was 4.0 +/- 3.5 nmol/mg protein/h in nineteen breast cancer tissue specimens, but was almost undetectable in eleven noncancerous mammary tissue specimens and eight benign breast lesions. These results suggest the relatively high local production of estrogen, mediated by aromatase or estrone sulfatase in breast cancer tissue.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mammary Stroma in Development and Carcinogenesis

Mammary glands of adult human females are secretory organs comprised of interdependent epithelial and mesenchymal cells. These cells constitute an assemblage of collecting ducts that end in terminal duct lobular units with hollow alveolar ductules that can differentiate to produce and expel milk. Systemic and maternal hormones, autocrine and paracrine growth factors, and cytokines regulate virtually all phases of mammary gland development. During organogenesis, epithelial and mesenchymal cells interact to form precursors of the parenchyma and stroma in the mature gland. Organogenesis precedes five stages of postnatal development: puberty, pregnancy, lactation, involution, and menopause. Each stage requires a specific set of morphogenetic changes in glandular structure and function. Cycles of cell proliferation, differentiation, and involution may recur until menopause. In addition, physiological responses such as inflammation and pathological events such as tumorigenesis are remarkable for their similarities to embryonic morphogenesis. Here we take a succinct look at the ever-improving understanding of stroma–epithelial interactions and mesenchyme function in mammary gland biology.     

Extracellular Proteolysis in Transgenic Mouse Models of Breast Cancer

Growth and invasion of breast cancer require extracellular proteolysis in order to physically restructure the tissue microenvironment of the mammary gland. This pathological tissue remodeling process depends on a collaboration of epithelial and stromal cells. In fact, the majority of extracellular proteases are provided by stromal cells rather than cancer cells. This distinct expression pattern is seen in human breast cancers and also in transgenic mouse models of breast cancer. The similar expression patterns suggest that transgenic mouse models are ideally suited to study the role of extracellular proteases in cancer progression. Here we give a status report on protease intervention studies in transgenic models. These studies demonstrate that proteases are involved in all stages of breast cancer progression from carcinogenesis to metastasis. Transgenic models are now beginning to provide vital mechanistic insight that will allow us to combat breast cancer invasion and metastasis with new protease-targeted drugs.     

Clusterin is not essential for androgen-regulated involution and regeneration of the normal mouse prostate

BACKGROUND: Inhibition of clusterin expression has been shown to enhance the sensitivity of prostate cancer cells to chemo and hormone therapy. Clusterin antisense oligonucleotides (ASOs) are currently in phase II human clinical trials for treatment of hormone refractory prostate cancer. However, the role of clusterin in androgen-regulated involution and regeneration of the normal prostate gland has not been established. METHODS: Prostate involution and regeneration was examined in clusterin-deficient mice undergoing up to three cycles of androgen withdrawal and restoration. RESULTS: Surprisingly, clusterin deficiency did not affect the apoptotic index, and the temporal biochemical and morphological changes associated with involution and regeneration of the normal adult prostate following multiple rounds of androgen withdrawal and replacement. CONCLUSION: Clusterin is not critical for normal prostate development or androgen-regulated involution and regrowth of the mouse prostate gland, suggesting that clusterin may have distinct functions in malignant versus normal prostatic epithelial cells.     

Short-term and long-term histologic effects of castration and estrogen treatment on breast tissue of 14 male-to-female transsexuals in comparison with two chemically castrated men

The histologic changes induced in the mammary gland of male-to-female transsexuals have not yet been reported in the literature. We studied the histologic changes induced by chemical and surgical castration and estrogen therapy in the breasts of 14 such patients, with particular reference to acinar and lobular formation. To objectify the influence of cross-sex treatment, the histologic findings were compared with those in two men treated hormonally for prostate cancer. The slight increase in the plasma estrogen-to-androgen ratio seen in idiopathic gynecomastia usually does not induce acinar and lobular formation in the male breast. In men treated with nonprogestative antiandrogens for prostate cancer, only moderate acinar and lobular formation occurs. Only in male-to-female transsexuals in whom progestative chemical castration is combined with feminizing estrogen therapy will full acinar and lobular formation occur with hormonally stimulated nuclei and pseudolactational changes. Hence, combined progestative antiandrogens and estrogens are necessary for genetically male breast tissue to mimic the natural histology of the female breast. Orchidectomy does not contribute to this. Apocrine metaplasia may occur in breasts of male-to-female transsexuals, but so far, only four cases of breast cancer in male-to-female transsexuals have been documented.     

Monitoring In-Vivo the Mammary Gland Microstructure during Morphogenesis from Lactation to Post-Weaning Using Diffusion Tensor MRI

Lactation and the return to the pre-conception state during post-weaning are regulated by hormonal induced processes that modify the microstructure of the mammary gland, leading to changes in the features of the ductal / glandular tissue, the stroma and the fat tissue. These changes create a challenge in the radiological workup of breast disorder during lactation and early post-weaning. Here we present non-invasive MRI protocols designed to record in vivo high spatial resolution, T₂-weighted images and diffusion tensor images of the entire mammary gland. Advanced imaging processing tools enabled tracking the changes in the anatomical and microstructural features of the mammary gland from the time of lactation to post-weaning. Specifically, by using diffusion tensor imaging (DTI) it was possible to quantitatively distinguish between the ductal / glandular tissue distention during lactation and the post-weaning involution. The application of the T₂-weighted imaging and DTI is completely safe, non-invasive and uses intrinsic contrast based on differences in transverse relaxation rates and water diffusion rates in various directions, respectively. This study provides a basis for further in-vivo monitoring of changes during the mammary developmental stages, as well as identifying changes due to malignant transformation in patients with pregnancy associated breast cancer (PABC).     

Hormonal Regulation of the Immune Microenvironment in the Mammary Gland

It is well established that the development and homeostasis of the mammary gland are highly dependent upon the actions of ovarian hormones progesterone and estrogen, as well as the availability of prolactin for the pregnant and lactating gland. More recently it has become apparent that immune system cells and cytokines play essential roles in both mammary gland development as well as breast cancer. Here, we review hormonal effects on mammary gland biology during puberty, menstrual cycling, pregnancy, lactation and involution, and dissect how hormonal control of the immune system may contribute to mammary development at each stage via cytokine secretion and recruitment of macrophages, eosinophils, mast cells and lymphocytes. Collectively, these alterations may create an immunotolerant or inflammatory immune environment at specific developmental stages or phases of the menstrual cycle. Of particular interest for further research is investigation of the combinatorial actions of progesterone and estrogen during the luteal phase of the menstrual cycle and key developmental points where the immune system may play an active role both in mammary development as well as in the creation of an immunotolerant environment, thereby affecting breast cancer risk.