Integumentary System - Mammary Gland Development
|Embryology - 20 Feb 2017 Expand to Translate|
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- 1 Introduction
- 2 Some Recent Findings
- 3 Textbooks
- 4 Development Overview
- 5 Anatomy
- 6 Puberty
- 7 Mammary Glands Pregnancy
- 8 Mammary Glands Weaning
- 9 Histology
- 10 Mouse Mammary
- 11 Abnormalities
- 12 International Classification of Diseases
- 13 References
- 14 Additional Images
- 15 External Links
- 16 Glossary Links
The mammary gland is the functional structure of the female breast and develops initially as a skin specialization. Breast growth and appearance in male and female children are virtually identical prior to puberty.
Postnatally at puberty female mammary glands under the influence of mainly sex hormone signaling, undergo a series of growth changes that can be defined anatomically by a series of "Tanner Stages". The bilayered mammary epithelium initially forms ducts that extend and branch.
In pregnancy, an additional series of signals leads to further changes in breast structure, differentiating into milk-producing alveoli. The key function of this process is to prepare the maternal breast for lactation and providing nutrition through milk to the newborn. (More? Normal Development - Milk)
Molecular signals identified as involved in this process include multiple Wnt ligands and β-catenin’s transcriptional activity for developmental processes and also for mammary stem cell self renewal.
At menopause, changes in sex hormone secretion can once again alter breast structure.
The breast also associated with oncogenesis (breast cancer). Research in this area has been aided by the discovery in 1994 of the two breast cancer susceptibility genes (BRCA1, BRCA2). There is some developing evidence that modification of stem cells (progenitor cells) that exist in the mammary gland may also contribute to neoplasms (cancer).
Some Recent Findings
|More recent papers|
This table shows an automated computer PubMed search using the listed sub-heading term.
References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.
Magdalena Matysiak, Lucyna Kapka-Skrzypczak, Barbara Jodłowska-Jędrych, Marcin Kruszewski EMT promoting transcription factors as prognostic markers in human breast cancer. Arch. Gynecol. Obstet.: 2017; PubMed 28190105
Ji Hoon Oh, Ho Hur, Ji-Yeon Lee, Yeejeong Kim, Younsoo Seo, Myoung Hee Kim The mitotic checkpoint regulator RAE1 induces aggressive breast cancer cell phenotypes by mediating epithelial-mesenchymal transition. Sci Rep: 2017, 7;42256 PubMed 28181567
Ohad Tarcic, Roy Z Granit, Ioannis S Pateras, Hadas Masury, Bella Maly, Yaara Zwang, Yosef Yarden, Vassilis G Gorgoulis, Eli Pikarsky, Ittai Ben-Porath, Moshe Oren RNF20 and histone H2B ubiquitylation exert opposing effects in Basal-Like versus luminal breast cancer. Cell Death Differ.: 2017; PubMed 28157208
Peipei Yan, Jingyi Xu, Yan Zeng, Guoying Dong, Huarong Cao, Meimei Zheng, Hui Zhu Long-term effects of repeated superovulation on the uterus and mammary gland in rhesus monkeys. J. Assist. Reprod. Genet.: 2017; PubMed 28116645
S Kau, I Miller, A Tichy, C Gabriel S100A4 (metastasin) positive mesenchymal canine mammary tumour spheroids reduce Tenascin C synthesis under DMSO exposure in vitro. Vet Comp Oncol: 2017; PubMed 28074628
- Human Embryology (2nd ed.) Larson Chapter 14 p443-455
- The Developing Human: Clinically Oriented Embryology (6th ed.) Moore and Persaud Chapter 20: P513-529
- Before We Are Born (5th ed.) Moore and Persaud Chapter 21: P481-496
- Essentials of Human Embryology Larson Chapter 14: P303-315
- Human Embryology, Fitzgerald and Fitzgerald
- Color Atlas of Clinical Embryology Moore Persaud and Shiota Chapter 15: p231-236
- week 6 epidermis downgrowth into dermis, modified sweat glands
- epithelia/mesenchyme inductive interaction, mesenchyme forms connective tissue and fat
- mammary ridges - mammary bud formation, pair of ventral regions axilla to inguinal
- pectoral regions generate breasts
- buds branch to form lactiferous ducts, only main duct formed at birth
- mammary pit - forms fetal period
- areola - depressed region at gland, proliferation of connective tissue postnatally
- prior to puberty male and female glands the same
| The mamma consists of gland tissue; of fibrous tissue, connecting its lobes; and of fatty tissue in the intervals between the lobes. The gland tissue, when freed from fibrous tissue and fat, is of a pale reddish color, firm in texture, flattened from before backward and thicker in the center than at the circumference.
(from Gray's Anatomy)
- sex hormone estrogen stimulate growth, full development approx 20 years
- growth also influenced by other hormones - progereterone, prolactin, corticoids, growth hormone
- mainly fat and connective tissue deposition
Tanner Mammary Development Stages
In 1976 Tanner and Whitehouse established a series of descriptive stages for primary and secondary sexual characteristic development at puberty. The female secondary sex characteristics of breast development were divided into five numbered (I - V) "Tanner Stages".
|Tanner Stage||Genitals (male)||Breasts (female)||Pubic hair (male and female)|
|prepubertal (testis volume < 1.5 ml
small penis (3 cm or less)
(age 9 and younger)
|no glandular tissue
areola follows the skin contours of the chest (prepubertal)
(age 10 and younger)
|no pubic hair at all (prepubertal state)|
(age 10 and younger)
|testis volume 1.6 to 6 ml
skin on scrotum thins, reddens and enlarges
penis length unchanged
|breast bud forms
with small area of surrounding glandular tissue
areola begins to widen
|small amount of long, downy hair with slight pigmentation at the base of the penis and scrotum (males) or on the labia majora (females)|
|testis volume 6 to 12 ml
scrotum enlarges further
penis begins to lengthen to about 6 cm
|breast begins to become more elevated
and extends beyond the borders of the areola, which continues to widen but remains in contour with surrounding breast
|hair becomes more coarse and curly|
begins to extend laterally
|testis volume 12 to 20 ml
scrotum enlarges further and darkens
penis increases in length to 10 cm and circumference
|increased breast size and elevation
areola and papilla form a secondary mound projecting from the contour of the surrounding breast
|adult–like hair quality|
extending across pubis but sparing medial thighs
||testis volume > 20 ml
adult scrotum and penis of 15 cm in length
|breast reaches final adult size
areola returns to contour of the surrounding breast
with a projecting central papilla
|hair extends to medial surface of the thighs|
|Links: Puberty Development | Genital System Development | Female | Male|
|Note that while typical ages are shown in brackets within the table, this is not a system for determining age.|
|Based upon W.A. Marshall and J.M. Tanner, published stages for girls (1969 ) and boys (1970 ).|
Mammary Glands Pregnancy
During pregnancy raised estrogens and progesterone stimulate gland development, secretory alveolar structures form and differentiate, leading to milk production in late pregnancy and milk secretion during lactation. Breasts are hemispherical in shape due to fat deposition. After birth, neonatal lactation supports further growth/development.
Mammary Glands Weaning
After the infant ceases breast feeding, weaning, the mammary gland milk-producing epithelial cells undergo a process called "involution", that requires cell apoptosis.
The mammary glands are modified glands of the skin and their development is similar to that of sweat glands.
- compound branched alveolar glands, secretory unit is the alveolus
- consist of 15-25 lobes separated by dense interlobar connective tissue and fat.
- each lobe contains an individual gland.
- lactiferous duct - excretory duct of each lobe with own opening on the nipple.
- inner layer of cuboidal secretory epithelial cells
- merocrine secretion, protein micelles are release by exocytosis.
- outer layer of myoepithelial cells
- located between the secretory cells and the surrounding basal lamina.
- contraction helps force the milk from the secretory alveoli into the ducts.
Note - plasma cells in the stroma also secrete antibodies (dimeric IgA) and released into the milk, to provides passive immunity to the suckling young.
|lactiferous duct||lactating mammary gland|
E10 - milk line first formed by a slight thickening and stratification of the surface ectoderm.
E10.5 - expression of Wnt10b in mammary lines on the trunk between the limbs and in axillary and inguinal streaks.
E11.5 - the milk line breaks up into individual placodes and the underlying mammary mesenchyme begins to condense.
E15.5 - mammary epithelium begins to proliferate at the tip and the primary sprout pushes through the mammary mesenchyme towards the underlying fat pad.
E18.5 - elongating duct has now grown into the fat pad and has branched into a small ductal system. Cells of the mammary mesenchyme have formed the nipple, which is made of specialized epidermal cells.
Timeline data from review
Canonical Wnt signals are transduced through a Frizzled receptor and the LRP5 or LRP6 co-receptor. Loss of Lrp6 compromises Wnt/beta-catenin signaling and interferes with mammary placode, fat pad, and branching development during embryogenesis.
Non-canonical receptor Ror2 along with its ligand Wnt5b (expressed in both the basal and luminal cell layers) regulates the branching, differentiation, and actin-cytoskeletal dynamics within the mammary epithelium.
Abnormalities occur in approximately 1% of female population and include in both sexes:
- polymastia - extra breast
- polytheli - extra nipple
- supernumerary nipple (relatively common in males)
- gynecomastia (Greek, gyne = woman, mastos = breast) is the excessive development of the male breast, which can occur transiently in puberty or due to other (hormonal) abnormalities.
International Classification of Diseases
Q83 Congenital malformations of breast
Excl.: absence of pectoral muscle (Q79.8)
- Q83.0 Congenital absence of breast with absent nipple
- Q83.1 Accessory breast Supernumerary breast
- Q83.2 Absent nipple
- Q83.3 Accessory nipple Supernumerary nipple
- Q83.8 Other congenital malformations of breast Hypoplasia of breast
- Q83.9 Congenital malformation of breast, unspecified
In 1994, two breast cancer susceptibility genes were identified BRCA1 on chromosome 17 and BRCA2 on chromosome 13.
When an individual carries a mutation in either BRCA1 or BRCA2, they are at an increased risk of being diagnosed with breast or ovarian cancer at some point in their lives. Normal function of these genes was to participate in repairing radiation-induced breaks in double-stranded DNA. It is though that mutations in BRCA1 or BRCA2 might disable this mechanism, leading to more errors in DNA replication and ultimately to cancerous growth. (text modified from: NCBI genes and disease)
BRAC1 and more recently BRIP1 (BRCA1-interacting protein 1) appear to be statistically the more common cancer genes associated with breast cancer.
Australia - Breast cancer in young women
26 Oct 2015 Key facts about breast cancer in women in their 20s and 30s
- In 2015, it is projected that 795 young women will be diagnosed with breast cancer and 65 will die from this disease.
- On average, this is more than 2 breast cancers diagnosed every day and more than 1 death every week.
- most commonly diagnosed cancer for women aged 20 to 39 and is associated with poorer survival outcomes.
- for women aged 40 and over, 40 new cases per day and 57 deaths per week-breast cancer.
- Overall, 5-year relative survival is significantly lower in younger women, who had an 88% chance of surviving for 5 years in 2007-2011 compared with the 5-year relative survival rate for women aged 40 and over of 90%. However, the 5-year relative survival rate has improved for young women, from 72% in 1982-1986 to 88% in 2007-2011.
- Links: Australian Statistics
- Krista Yorita Christensen, Mildred Maisonet, Carol Rubin, W Dana Flanders, Carolyn Drews-Botsch, Celia Dominguez, Michael A McGeehin, Michele Marcus Characterization of the correlation between ages at entry into breast and pubic hair development. Ann Epidemiol: 2010, 20(5);405-8 PubMed 20382343
- Dara Cannata, Danielle Lann, Yingjie Wu, Sebastien Elis, Hui Sun, Shoshana Yakar, Deborah A Lazzarino, Teresa L Wood, Derek Leroith Elevated circulating IGF-I promotes mammary gland development and proliferation. Endocrinology: 2010, 151(12);5751-61 PubMed 20926579
- Pepper Schedin, Russell C Hovey Editorial: The mammary stroma in normal development and function. J Mammary Gland Biol Neoplasia: 2010, 15(3);275-7 PubMed 20824491
- J M Tanner, R H Whitehouse Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty. Arch. Dis. Child.: 1976, 51(3);170-9 PubMed 952550
- W A Marshall, J M Tanner Variations in pattern of pubertal changes in girls. Arch. Dis. Child.: 1969, 44(235);291-303 PubMed 5785179
- W A Marshall, J M Tanner Variations in the pattern of pubertal changes in boys. Arch. Dis. Child.: 1970, 45(239);13-23 PubMed 5440182
- Christine J Watson Involution: apoptosis and tissue remodelling that convert the mammary gland from milk factory to a quiescent organ. Breast Cancer Res.: 2006, 8(2);203 PubMed 16677411 | Breast Cancer Res.
- Beatrice Howard, Alan Ashworth Signalling pathways implicated in early mammary gland morphogenesis and breast cancer. PLoS Genet.: 2006, 2(8);e112 PubMed 16933995 | PLoS Genet.
- Gertraud W Robinson Cooperation of signalling pathways in embryonic mammary gland development. Nat. Rev. Genet.: 2007, 8(12);963-72 PubMed 18007652
- Charlotta Lindvall, Cassandra R Zylstra, Nicole Evans, Richard A West, Karl Dykema, Kyle A Furge, Bart O Williams The Wnt co-receptor Lrp6 is required for normal mouse mammary gland development. PLoS ONE: 2009, 4(6);e5813 PubMed 19503830
- Kevin Roarty, Amy N Shore, Chad J Creighton, Jeffrey M Rosen Ror2 regulates branching, differentiation, and actin-cytoskeletal dynamics within the mammary epithelium. J. Cell Biol.: 2015; PubMed 25624393 | J Cell Biol.
- AIHW 2015. Breast cancer in young women: key facts about breast cancer in women in their 20s and 30s. Cancer series no. 96. Cat. no. CAN 94. Canberra: AIHW. http://www.aihw.gov.au/publication-detail/?id=60129553359
Christophe M Lefèvre, Julie A Sharp, Kevin R Nicholas Evolution of lactation: ancient origin and extreme adaptations of the lactation system. Annu Rev Genomics Hum Genet: 2010, 11;219-38 PubMed 20565255
Pamela Cowin, John Wysolmerski Molecular mechanisms guiding embryonic mammary gland development. Cold Spring Harb Perspect Biol: 2010, 2(6);a003251 PubMed 20484386
Constantine Dimitrakakis, Carolyn Bondy Androgens and the breast. Breast Cancer Res.: 2009, 11(5);212 PubMed 19889198
Anne M Rowzee, Deborah A Lazzarino, Lauren Rota, Zhaoyu Sun, Teresa L Wood IGF ligand and receptor regulation of mammary development. J Mammary Gland Biol Neoplasia: 2008, 13(4);361-70 PubMed 19020961
Heather L LaMarca, Jeffrey M Rosen Minireview: hormones and mammary cell fate--what will I become when I grow up? Endocrinology: 2008, 149(9);4317-21 PubMed 18556345
M M Richert, K L Schwertfeger, J W Ryder, S M Anderson An atlas of mouse mammary gland development. J Mammary Gland Biol Neoplasia: 2000, 5(2);227-41 PubMed 11149575
Radhika Nair, Simon Junankar, Sandra O'Toole, Jaynish Shah, Alexander D Borowsky, J Michael Bishop, Alexander Swarbrick Redefining the expression and function of the inhibitor of differentiation 1 in mammary gland development. PLoS ONE: 2010, 5(8);e11947 PubMed 20689821
Thomas W Owens, Fiona M Foster, Jolanta Tanianis-Hughes, Julia Y Cheung, Lisa Brackenbury, Charles H Streuli Analysis of inhibitor of apoptosis protein family expression during mammary gland development. BMC Dev. Biol.: 2010, 10;71 PubMed 20584313
Nicholas McCormick, Vanessa Velasquez, Lydia Finney, Stefan Vogt, Shannon L Kelleher X-ray fluorescence microscopy reveals accumulation and secretion of discrete intracellular zinc pools in the lactating mouse mammary gland. PLoS ONE: 2010, 5(6);e11078 PubMed 20552032
| PLoS One. Holly E Barker, Gordon K Smyth, James Wettenhall, Teresa A Ward, Mary L Bath, Geoffrey J Lindeman, Jane E Visvader Deaf-1 regulates epithelial cell proliferation and side-branching in the mammary gland. BMC Dev. Biol.: 2008, 8;94 PubMed 18826651
D T Ramsay, J C Kent, R A Hartmann, P E Hartmann Anatomy of the lactating human breast redefined with ultrasound imaging. J. Anat.: 2005, 206(6);525-34 PubMed 15960763
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