Integumentary System - Mammary Gland Development

Introduction

Adult female mammary anatomy cartoon

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.

At puberty females, under the influence of mainly sex hormone signaling, undergo a series of growth changes that can be defined by a series of "Tanner Stages".

In pregnancy, an additional series of signals leads to further changes in breast structure. 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)

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).

Integumentary Links: Introduction | Lecture | Hair | Tooth | Nail | Gland | Mammary Gland | Eyelid | Outer Ear | Touch | Histology | Abnormalities | Category:Integumentary

Historic Embryology: 1910 Manual of Human Embryology | 1923 Head Subcutaneous Plexus | 1921 Text-Book of Embryology | Historic Disclaimer

Normal Development - Milk

Some Recent Findings

Characterization of the correlation between ages at entry into breast and pubic hair development "Among 3938 participants, estimated mean ages at entry into Tanner stage 2 for breast and pubic hair development were 10.19 and 10.95, respectively." Elevated Circulating IGF-I Promotes Mammary Gland Development and Proliferation"Animal studies have shown that Insulin-like growth factor 1 (IGF-1, somatomedin-C) is essential for mammary gland development. Previous studies have suggested that local IGF-I rather than circulating IGF-I is the major mediator of mammary gland development. " Editorial: The Mammary Stroma in Normal Development and Function "Many lines of evidence have evolved to reinforce the notion that mammary epithelial cell growth, differentiation, lactation and progression to cancer involves bidirectional interactions between the epithelial population and its surrounding stroma. ...the stromal environment constitutes and supports a critical vasculature that supplies nutrients and endocrine cues, a lymphatic system that not only removes metabolites but also provides an intimate interface with the immune system, and an extracellular matrix scaffold in which epithelial cells grow, differentiate and regress."

Textbooks

• 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

Development Overview

• 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

Puberty

• 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 (1 - 5) "Tanner Stages".

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.

Mammary involution]

Mouse Mammary

Mouse mammary gland development (E14.5)

E10 - milk line first formed by a slight thickening and stratification of the surface ectoderm.

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

Related Mouse Mammary Images: E10/11 | E11 | E12 | E13 | E14.5

Wnt Signaling

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.

Links: Mouse Timeline Detailed

Abnormalities

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

ICD-10 Code: Q83 Congenital malformations of breast

Breast Cancer

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)

Links: OMIM - BRCA1 | OMIM - BRCA2

References

Reviews

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 PMID:20565255

Pamela Cowin, John Wysolmerski Molecular mechanisms guiding embryonic mammary gland development. Cold Spring Harb Perspect Biol: 2010, 2(6);a003251 PMID:20484386

Constantine Dimitrakakis, Carolyn Bondy Androgens and the breast. Breast Cancer Res.: 2009, 11(5);212 PMID: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 PMID: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 PMID:18556345

Articles

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 PMID: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 PMID: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 PMID: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 PMID:18826651

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