Mammogenesis

The lifespan changes of the human mammary gland are referred to as mammogenesis, lactogenesis, galactopoiesis, and involution.

Sufficient breast development, or mammogenesis, is a fundamental prerequisite for optimal milk production capacity. From birth to puberty, rudimentary lactiferous duct branches elongate through the mammary fat pad and form terminal end buds in preparation for activation during pregnancy and lactation.

Mechanical cues direct branching morphogenesis during the development, and mechanical cues strongly influence stem cell differentiation. "Each stage of mammary gland development has a unique mechanical environment that may influence tissue architecture. ... The mechanical forces in mammary gland are integrated within a complex network of hormonal and biochemical signals" (Boyle et al 2021).

Pubertal mammary gland

Critical windows in mammary development occur around puberty. In puberty, breast development is characterised by

• Further development of terminal end buds

• Ductal elongation

• Ductal side-branching.

The expansion of the ductal system into a highly branched tubular structure is embedded within an adipose stroma. Again, mechanical cues strongly influence this development.

Adult mammary gland

Adult mammary epithelium is a fully arborized ductal network embedded within the adipose stroma. Ductal epithelium contains both luminal and surrounding basal (or myoepithelial) cells.

Conception to onset of secretory differentiation phase of lactogenesis

From conception through the first trimester of pregnancy, there is rapid growth of the ductal-lobular-alveolar system in the woman's breasts. Colostral milk is first secreted into the developing alveoli between 16-22 weeks gestation, marking the beginning of lactogenesis.

Slide 23 in Dr Kate Rassie's talk on Diabetes, PCOS and breastfeeding is an excellent illustration of the time frames of mammogenesis, lactogenesis, and galactopoiesis, found here.

You can find out about lactogenesis here.

Involution

Weaning commences with the introduction of infant solids, typically at or around six months of age, because milk secretion declines as solid intake increases.

With gradual weaning, the homeostatic balance of local control is tipped so that lactocyte apoptosis exceeds mammary epithelial cell proliferation. With increased mammary epithelial cell apoptosis, inflammatory activity within the mammary gland increases, resulting in tissue remodeling.

Milk accumulation leads to intraluminal pressure build-up. The resulting epithelial cell stretching is hypothesised to contribute to cellular events such as leukemia inhibitory factor expression and STAT3 activation which define the initiation of involution.

Complete weaning is known to

• Switch off the systemic hormones which have prepared (in lactogenesis) and maintained (in galactopoiesis) the glandular terrain required for lactation

• Cause widespread cell apoptosis including of mammary epithelial cells, which results widespread microscopic and subclinical exacerbation of inflammation. Involution after complete weaning is one of the largest physiological cell death cascades that occurs postnally in mammals. The mammary gland tissue then remodels back to an inactive, involuted, between-pregnancy state. The very active inflammatory processes found in the breast after complete weaning settle after about a month, when remodelling of the breast tissue back into a quiescent state is largely completed.

• "However, the pregnancy-lactation-involution cycle can permanently alter both mammary epithelial cells and the extracellular matrix composition, a phenomenon that may influence the lifetime risk of tumor development in this organ." (Stewart et al 2021)

The NDC mechanobiological model of breast inflammation argues that the same mechanism which causes the apoptosis which underlies weaning is associated with downregulation of milk production throughout the course of lactation, and also underlies clinical presentations of breast inflammation and also downregulation of milk secretion.

Selected references

Anderson SM, Rudolph MC, McManaman JL, Neville MC. Key stages in mammary gland development. Secretory activation in the mammary gland: it’s not just about milk protein synthesis! Breast Cancer Res 2007;9(1):204.

Boyle ST, Poltavets V, Samuel MS. Mechanical signaling in the mammary microenvironment: from homeostasis to cancer. In: Birbrair A, editor. Tumor Microenvironment Advances in Experimental Medicine and Biology. 1329. Cham.: Springer; 2021. p. https://doi.org/10.1007/1978-1003-1030-73119-73119_73119.

Folley SJ. Symposium on lactogenesis: chairman’s introduction. In: Reynolds M, Folley SJ, editors Lactogenesis: the initiation of milk secretion at parturition. Philadelphia: Pennsylvania Press; 1969. p. 1–3.

Geddes DT, Gridneva Z, Perrella SL, Mitoulas LR, Kent JC, Stinson LF, et al. 25 years of research in human lactation: from discovery to translation. Nutrients. 2021;13:1307.

Lee S, Kelleher SL. Biological underpinnings of breastfeeding challenges: the role of genetics, diet, and environment on lactation physiology. American Journal of Physiology - Endocrinology and Metabolism. 2016;311:E405–E422.

Pang WW, Hartmann PE. Initiation of human lactation: secretory differentiation and secretory activation. Journal of Mammary Gland Biology and Neoplasia. 2007;12:211-221.

Ramsay DT, Kent JC, Hartmann RA, Hartmann PE. Anatomy of the lactating human breast redefined with ultrasound imaging. J Anat 206: 525–534, 2005.